Identification

Name
Brigatinib
Accession Number
DB12267
Type
Small Molecule
Groups
Approved, Investigational
Description

Brigatinib, originally named AP26113, is a reversible dual inhibitor of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR). It presents selectivity against the mutant forms of EGFR compared to the wild-type.[1] It also exhibits selectivity against 9 different Crizotinib-resistant mutants of the EML4-ALK fusion gene, which is a pivotal player in the transformation of susceptible lung parenchyma.[2] Brigatinib was developed by Ariad Pharmaceuticals, a subsidiary of Takeda Pharmaceutical Company Limited, and FDA-approved on April 28, 2017.[9]

Structure
Thumb
Synonyms
Not Available
External IDs
AP-26113 / AP26113
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlunbrigTablet, coated30 mg/1OralAriad Pharmaceuticals Inc.2017-04-28Not applicableUs
AlunbrigTablet, film coated30 mg/1OralMillennium Pharmaceuticals, Inc.2017-04-28Not applicableUs
AlunbrigKitMillennium Pharmaceuticals, Inc.2017-04-28Not applicableUs
AlunbrigTablet, film coated90 mg/1OralMillennium Pharmaceuticals, Inc.2017-04-28Not applicableUs
AlunbrigTablet, film coated180 mg/1OralMillennium Pharmaceuticals, Inc.2017-04-28Not applicableUs
Categories
UNII
HYW8DB273J
CAS number
1197953-54-0
Weight
Average: 584.1
Monoisotopic: 583.2591382
Chemical Formula
C29H39ClN7O2P
InChI Key
AILRADAXUVEEIR-UHFFFAOYSA-N
InChI
InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)
IUPAC Name
5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine
SMILES
COC1=CC(=CC=C1NC1=NC=C(Cl)C(NC2=CC=CC=C2P(C)(C)=O)=N1)N1CCC(CC1)N1CCN(C)CC1

Pharmacology

Indication

The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target.[1] The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules.[2] The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival.[4] Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib.[3]

Associated Conditions
Pharmacodynamics

Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y.[5] Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models.[6] Time course of Brigatinib and exposure-response studies are still unknown.

Mechanism of action

Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling proteins.[7]

TargetActionsOrganism
AALK tyrosine kinase receptor
inhibitor
Human
AEpidermal growth factor receptor
inhibitor
Human
UTyrosine-protein kinase ABL1
inhibitor
Human
UInsulin-like growth factor 1 receptor
inhibitor
Human
UReceptor-type tyrosine-protein kinase FLT3
inhibitor
Human
NInsulin receptor
binding
Human
UHepatocyte growth factor receptor
inhibitor
Human
UReceptor tyrosine-protein kinase erbB-4
inhibitor
Human
UReceptor tyrosine-protein kinase erbB-2
inhibitor
Human
Absorption

Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC.[8]

Volume of distribution

The apparent volume of distribution at steady state is 153 L.[8]

Protein binding

66% of brigatinib dose is bound to plasma proteins, which gives a blood-to-plasma concentration ratio of 0.69.[8]

Metabolism

Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower.[10]

Route of elimination

The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% in urine.[10]

Half life

The half-life of brigatinib at steady-state was 25 hours.[10]

Clearance

After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h.[10]

Toxicity

Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis.[FDA Label]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AbirateroneThe serum concentration of Brigatinib can be increased when it is combined with Abiraterone.Approved
Acetyl sulfisoxazoleThe metabolism of Brigatinib can be decreased when combined with Acetyl sulfisoxazole.Approved, Vet Approved
AlfentanilThe serum concentration of Alfentanil can be decreased when it is combined with Brigatinib.Approved, Illicit
AlprazolamThe serum concentration of Alprazolam can be decreased when it is combined with Brigatinib.Approved, Illicit, Investigational
AmiodaroneThe metabolism of Brigatinib can be decreased when combined with Amiodarone.Approved, Investigational
ApalutamideThe serum concentration of Brigatinib can be decreased when it is combined with Apalutamide.Approved, Investigational
AprepitantThe serum concentration of Aprepitant can be decreased when it is combined with Brigatinib.Approved, Investigational
AtazanavirThe metabolism of Brigatinib can be decreased when combined with Atazanavir.Approved, Investigational
AtomoxetineThe metabolism of Brigatinib can be decreased when combined with Atomoxetine.Approved
AtorvastatinThe serum concentration of Atorvastatin can be decreased when it is combined with Brigatinib.Approved
AvanafilThe serum concentration of Avanafil can be decreased when it is combined with Brigatinib.Approved
BoceprevirThe serum concentration of Brigatinib can be increased when it is combined with Boceprevir.Approved, Withdrawn
BortezomibThe metabolism of Brigatinib can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Brigatinib can be decreased when it is combined with Bosentan.Approved, Investigational
BudesonideThe serum concentration of Budesonide can be decreased when it is combined with Brigatinib.Approved
BuspironeThe serum concentration of Buspirone can be decreased when it is combined with Brigatinib.Approved, Investigational
CarbamazepineThe serum concentration of Brigatinib can be decreased when it is combined with Carbamazepine.Approved, Investigational
CelecoxibThe metabolism of Brigatinib can be decreased when combined with Celecoxib.Approved, Investigational
CeritinibThe serum concentration of Brigatinib can be increased when it is combined with Ceritinib.Approved
ClarithromycinThe serum concentration of Brigatinib can be increased when it is combined with Clarithromycin.Approved
ClemastineThe metabolism of Brigatinib can be decreased when combined with Clemastine.Approved, Investigational
ClotrimazoleThe metabolism of Brigatinib can be decreased when combined with Clotrimazole.Approved, Vet Approved
CobicistatThe serum concentration of Brigatinib can be increased when it is combined with Cobicistat.Approved
ColchicineThe serum concentration of Colchicine can be decreased when it is combined with Brigatinib.Approved
ConivaptanThe serum concentration of Conivaptan can be increased when it is combined with Brigatinib.Approved, Investigational
CrisaboroleThe metabolism of Brigatinib can be decreased when combined with Crisaborole.Approved, Investigational
CrizotinibThe metabolism of Brigatinib can be decreased when combined with Crizotinib.Approved
CurcuminThe metabolism of Brigatinib can be decreased when combined with Curcumin.Approved, Investigational
CyclosporineThe metabolism of Brigatinib can be decreased when combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Brigatinib can be decreased when it is combined with Dabrafenib.Approved, Investigational
DarifenacinThe serum concentration of Darifenacin can be decreased when it is combined with Brigatinib.Approved, Investigational
DarunavirThe serum concentration of Darunavir can be decreased when it is combined with Brigatinib.Approved
DasatinibThe serum concentration of Dasatinib can be decreased when it is combined with Brigatinib.Approved, Investigational
DeferasiroxThe serum concentration of Brigatinib can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Brigatinib can be decreased when combined with Delavirdine.Approved
DihydroergotamineThe metabolism of Brigatinib can be decreased when combined with Dihydroergotamine.Approved, Investigational
DiltiazemThe metabolism of Brigatinib can be decreased when combined with Diltiazem.Approved, Investigational
DoxycyclineThe metabolism of Brigatinib can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe serum concentration of Dronedarone can be decreased when it is combined with Brigatinib.Approved
EbastineThe serum concentration of Ebastine can be decreased when it is combined with Brigatinib.Approved, Investigational
EfavirenzThe metabolism of Brigatinib can be decreased when combined with Efavirenz.Approved, Investigational
EletriptanThe serum concentration of Eletriptan can be decreased when it is combined with Brigatinib.Approved, Investigational
EliglustatThe serum concentration of Eliglustat can be decreased when it is combined with Brigatinib.Approved
EltrombopagThe serum concentration of Brigatinib can be increased when it is combined with Eltrombopag.Approved
EnzalutamideThe serum concentration of Brigatinib can be decreased when it is combined with Enzalutamide.Approved
EplerenoneThe serum concentration of Eplerenone can be decreased when it is combined with Brigatinib.Approved
ErythromycinThe metabolism of Brigatinib can be decreased when combined with Erythromycin.Approved, Investigational, Vet Approved
EverolimusThe serum concentration of Everolimus can be decreased when it is combined with Brigatinib.Approved
FelodipineThe serum concentration of Felodipine can be decreased when it is combined with Brigatinib.Approved, Investigational
FluconazoleThe metabolism of Brigatinib can be decreased when combined with Fluconazole.Approved, Investigational
FluvoxamineThe metabolism of Brigatinib can be decreased when combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Brigatinib can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Brigatinib can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe metabolism of Brigatinib can be increased when combined with Fosphenytoin.Approved, Investigational
Fusidic AcidThe serum concentration of Brigatinib can be increased when it is combined with Fusidic Acid.Approved, Investigational
IbrutinibThe serum concentration of Ibrutinib can be decreased when it is combined with Brigatinib.Approved
IdelalisibThe metabolism of Brigatinib can be decreased when combined with Idelalisib.Approved
ImatinibThe metabolism of Brigatinib can be decreased when combined with Imatinib.Approved
IndinavirThe serum concentration of Brigatinib can be increased when it is combined with Indinavir.Approved
IrbesartanThe metabolism of Brigatinib can be decreased when combined with Irbesartan.Approved, Investigational
IsavuconazoleThe serum concentration of Brigatinib can be increased when it is combined with Isavuconazole.Approved, Investigational
IsavuconazoniumThe metabolism of Brigatinib can be decreased when combined with Isavuconazonium.Approved, Investigational
IsradipineThe metabolism of Brigatinib can be decreased when combined with Isradipine.Approved, Investigational
ItraconazoleThe serum concentration of Brigatinib can be increased when it is combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Brigatinib can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe serum concentration of Brigatinib can be increased when it is combined with Ketoconazole.Approved, Investigational
LapatinibThe metabolism of Brigatinib can be decreased when combined with Lapatinib.Approved, Investigational
LomitapideThe serum concentration of Lomitapide can be decreased when it is combined with Brigatinib.Approved, Investigational
LopinavirThe serum concentration of Brigatinib can be increased when it is combined with Lopinavir.Approved
LorpiprazoleThe serum concentration of Brigatinib can be increased when it is combined with Lorpiprazole.Approved
LosartanThe metabolism of Brigatinib can be decreased when combined with Losartan.Approved
LovastatinThe serum concentration of Lovastatin can be decreased when it is combined with Brigatinib.Approved, Investigational
LuliconazoleThe serum concentration of Brigatinib can be increased when it is combined with Luliconazole.Approved
LumacaftorThe serum concentration of Brigatinib can be increased when it is combined with Lumacaftor.Approved
LurasidoneThe serum concentration of Lurasidone can be decreased when it is combined with Brigatinib.Approved, Investigational
MaravirocThe serum concentration of Maraviroc can be decreased when it is combined with Brigatinib.Approved, Investigational
MidazolamThe serum concentration of Midazolam can be decreased when it is combined with Brigatinib.Approved, Illicit
MifepristoneThe serum concentration of Brigatinib can be increased when it is combined with Mifepristone.Approved, Investigational
MitotaneThe serum concentration of Brigatinib can be decreased when it is combined with Mitotane.Approved
NabiloneThe metabolism of Brigatinib can be decreased when combined with Nabilone.Approved, Investigational
NaloxegolThe serum concentration of Naloxegol can be decreased when it is combined with Brigatinib.Approved
NefazodoneThe metabolism of Brigatinib can be decreased when combined with Nefazodone.Approved, Withdrawn
NelfinavirThe serum concentration of Brigatinib can be increased when it is combined with Nelfinavir.Approved
NetupitantThe serum concentration of Brigatinib can be increased when it is combined with Netupitant.Approved, Investigational
NevirapineThe metabolism of Brigatinib can be increased when combined with Nevirapine.Approved
NilotinibThe metabolism of Brigatinib can be decreased when combined with Nilotinib.Approved, Investigational
NisoldipineThe serum concentration of Nisoldipine can be decreased when it is combined with Brigatinib.Approved
OlaparibThe metabolism of Brigatinib can be decreased when combined with Olaparib.Approved
OsimertinibThe serum concentration of Brigatinib can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Brigatinib can be increased when it is combined with Palbociclib.Approved, Investigational
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Brigatinib.Approved
PentobarbitalThe metabolism of Brigatinib can be increased when combined with Pentobarbital.Approved, Investigational, Vet Approved
PhenobarbitalThe metabolism of Brigatinib can be increased when combined with Phenobarbital.Approved, Investigational
PhenytoinThe serum concentration of Brigatinib can be decreased when it is combined with Phenytoin.Approved, Vet Approved
PimozideThe serum concentration of Pimozide can be decreased when it is combined with Brigatinib.Approved
PioglitazoneThe metabolism of Brigatinib can be decreased when combined with Pioglitazone.Approved, Investigational
PitolisantThe serum concentration of Brigatinib can be decreased when it is combined with Pitolisant.Approved, Investigational
PosaconazoleThe serum concentration of Brigatinib can be increased when it is combined with Posaconazole.Approved, Investigational, Vet Approved
PrimidoneThe metabolism of Brigatinib can be increased when combined with Primidone.Approved, Vet Approved
QuetiapineThe serum concentration of Quetiapine can be decreased when it is combined with Brigatinib.Approved
QuinineThe metabolism of Brigatinib can be decreased when combined with Quinine.Approved
RabeprazoleThe metabolism of Brigatinib can be decreased when combined with Rabeprazole.Approved, Investigational
RanolazineThe metabolism of Brigatinib can be decreased when combined with Ranolazine.Approved, Investigational
RifabutinThe metabolism of Brigatinib can be increased when combined with Rifabutin.Approved, Investigational
RifampicinThe serum concentration of Brigatinib can be decreased when it is combined with Rifampicin.Approved
RifapentineThe metabolism of Brigatinib can be increased when combined with Rifapentine.Approved, Investigational
RilpivirineThe serum concentration of Rilpivirine can be decreased when it is combined with Brigatinib.Approved
RivaroxabanThe serum concentration of Rivaroxaban can be decreased when it is combined with Brigatinib.Approved
RolapitantThe serum concentration of Brigatinib can be increased when it is combined with Rolapitant.Approved, Investigational
RosiglitazoneThe metabolism of Brigatinib can be decreased when combined with Rosiglitazone.Approved, Investigational
RucaparibThe metabolism of Brigatinib can be decreased when combined with Rucaparib.Approved, Investigational
SaquinavirThe serum concentration of Brigatinib can be increased when it is combined with Saquinavir.Approved, Investigational
SarilumabThe therapeutic efficacy of Brigatinib can be decreased when used in combination with Sarilumab.Approved, Investigational
SecobarbitalThe metabolism of Brigatinib can be increased when combined with Secobarbital.Approved, Vet Approved
SildenafilThe serum concentration of Sildenafil can be decreased when it is combined with Brigatinib.Approved, Investigational
SiltuximabThe serum concentration of Brigatinib can be decreased when it is combined with Siltuximab.Approved, Investigational
SimeprevirThe serum concentration of Brigatinib can be increased when it is combined with Simeprevir.Approved
SimvastatinThe serum concentration of Simvastatin can be decreased when it is combined with Brigatinib.Approved
SirolimusThe serum concentration of Sirolimus can be decreased when it is combined with Brigatinib.Approved, Investigational
St. John's WortThe serum concentration of Brigatinib can be decreased when it is combined with St. John's Wort.Approved, Investigational, Nutraceutical
StiripentolThe serum concentration of Brigatinib can be increased when it is combined with Stiripentol.Approved
SulfamethoxazoleThe metabolism of Brigatinib can be decreased when combined with Sulfamethoxazole.Approved
SulfisoxazoleThe metabolism of Brigatinib can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TacrolimusThe serum concentration of Tacrolimus can be decreased when it is combined with Brigatinib.Approved, Investigational
TadalafilThe serum concentration of Tadalafil can be decreased when it is combined with Brigatinib.Approved, Investigational
TamoxifenThe metabolism of Brigatinib can be decreased when combined with Tamoxifen.Approved
TelaprevirThe metabolism of Brigatinib can be decreased when combined with Telaprevir.Approved, Withdrawn
TelithromycinThe metabolism of Brigatinib can be decreased when combined with Telithromycin.Approved
TeriflunomideThe serum concentration of Brigatinib can be increased when it is combined with Teriflunomide.Approved
TicagrelorThe serum concentration of Ticagrelor can be decreased when it is combined with Brigatinib.Approved
TiclopidineThe metabolism of Brigatinib can be decreased when combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Brigatinib can be decreased when it is combined with Tocilizumab.Approved
TolvaptanThe serum concentration of Tolvaptan can be decreased when it is combined with Brigatinib.Approved
TopiroxostatThe metabolism of Brigatinib can be decreased when combined with Topiroxostat.Approved, Investigational
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Brigatinib.Approved, Investigational
TriazolamThe serum concentration of Triazolam can be decreased when it is combined with Brigatinib.Approved, Investigational
TrimethoprimThe metabolism of Brigatinib can be decreased when combined with Trimethoprim.Approved, Vet Approved
VardenafilThe serum concentration of Vardenafil can be decreased when it is combined with Brigatinib.Approved
VemurafenibThe serum concentration of Brigatinib can be decreased when it is combined with Vemurafenib.Approved
VenlafaxineThe metabolism of Brigatinib can be decreased when combined with Venlafaxine.Approved
VerapamilThe metabolism of Brigatinib can be decreased when combined with Verapamil.Approved
VoriconazoleThe serum concentration of Brigatinib can be increased when it is combined with Voriconazole.Approved, Investigational
ZiprasidoneThe metabolism of Brigatinib can be decreased when combined with Ziprasidone.Approved
Food Interactions
Not Available

References

General References
  1. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C: Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013 Feb;11(2):122-32. doi: 10.1158/1541-7786.MCR-12-0569. Epub 2012 Dec 13. [PubMed:23239810]
  2. Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, Liu D: Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015 Feb 27;8:17. doi: 10.1186/s13045-015-0122-8. [PubMed:25888090]
  3. Rashdan S, Gerber DE: A crowded, but still varied, space: brigatinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Transl Cancer Res. 2017 Feb;6(Suppl 1):S78-S82. doi: 10.21037/tcr.2017.02.12. [PubMed:28680831]
  4. Sabir SR, Yeoh S, Jackson G, Bayliss R: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients. Cancers (Basel). 2017 Sep 5;9(9). pii: E118. doi: 10.3390/cancers9090118. [PubMed:28872581]
  5. Sabari JK, Santini FC, Schram AM, Bergagnini I, Chen R, Mrad C, Lai WV, Arbour KC, Drilon A: The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers. Onco Targets Ther. 2017 Apr 6;10:1983-1992. doi: 10.2147/OTT.S109295. eCollection 2017. [PubMed:28435288]
  6. Siaw JT, Wan H, Pfeifer K, Rivera VM, Guan J, Palmer RH, Hallberg B: Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice. Oncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508. [PubMed:27049722]
  7. Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC: Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem. 2016 May 26;59(10):4948-64. doi: 10.1021/acs.jmedchem.6b00306. Epub 2016 May 12. [PubMed:27144831]
  8. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
  9. FDA News and Events [Link]
  10. FDA Reports [Link]
External Links
PubChem Compound
68165256
PubChem Substance
347828538
ChemSpider
34982928
BindingDB
50185140
ChEMBL
CHEMBL3545311
PharmGKB
PA166163482
HET
6GY
Wikipedia
Brigatinib
PDB Entries
5j7h
FDA label
Download (595 KB)
MSDS
Download (25.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Not Yet RecruitingOtherCarcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors1
1, 2Active Not RecruitingTreatmentAdvanced Malignancies / Anaplastic Large Cell Lymphoma / Diffuse Large Cell Lymphoma / Inflammatory Myofibroblastic Tumors / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lymphoma, Large-Cell, Anaplastic1
2Active Not RecruitingTreatmentAdvanced Malignancies / Carcinoma NOS / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers1
2Not Yet RecruitingTreatmentALK-positive Advanced NSCLC1
2RecruitingTreatmentALK-positive Advanced NSCLC1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
3Active Not RecruitingTreatmentAdvanced Malignancies / Carcinoma NOS / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers1
Not AvailableNo Longer AvailableNot AvailableAdvanced Malignancies / Carcinoma NOS / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers1
Not AvailableNot Yet RecruitingNot AvailableAnaplastic Lymphoma Kinase-positive / Carcinoma Non-small-cell Lung1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit
Tablet, coatedOral30 mg/1
Tablet, film coatedOral180 mg/1
Tablet, film coatedOral30 mg/1
Tablet, film coatedOral90 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9012462No2011-02-062031-02-06Us
US9611283No2014-04-102034-04-10Us
US9273077No2009-05-212029-05-21Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolubleSelleckchem, MSDS
logP5.17Molbase, MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.022 mg/mLALOGPS
logP5.11ALOGPS
logP3.66ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)12.88ChemAxon
pKa (Strongest Basic)8.54ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area85.86 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity164.77 m3·mol-1ChemAxon
Polarizability64.1 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Aminophenyl ethers / Methoxyanilines / Phenoxy compounds / Anisoles / Dialkylarylamines / Methoxybenzenes / Alkyl aryl ethers / Phenylphosphines and derivatives / Aminopiperidines / Aminopyrimidines and derivatives
show 13 more
Substituents
Phenylpiperidine / Aminophenyl ether / Methoxyaniline / Anisole / Phenoxy compound / Phenol ether / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Aniline or substituted anilines / Methoxybenzene
show 34 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis a...
Gene Name
ALK
Uniprot ID
Q9UM73
Uniprot Name
ALK tyrosine kinase receptor
Molecular Weight
176440.535 Da
References
  1. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C: Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013 Feb;11(2):122-32. doi: 10.1158/1541-7786.MCR-12-0569. Epub 2012 Dec 13. [PubMed:23239810]
  2. Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, Liu D: Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015 Feb 27;8:17. doi: 10.1186/s13045-015-0122-8. [PubMed:25888090]
  3. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C: Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013 Feb;11(2):122-32. doi: 10.1158/1541-7786.MCR-12-0569. Epub 2012 Dec 13. [PubMed:23239810]
  2. Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, Liu D: Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015 Feb 27;8:17. doi: 10.1186/s13045-015-0122-8. [PubMed:25888090]
  3. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Syntaxin binding
Specific Function
Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility a...
Gene Name
ABL1
Uniprot ID
P00519
Uniprot Name
Tyrosine-protein kinase ABL1
Molecular Weight
122871.435 Da
References
  1. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
  2. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C: Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013 Feb;11(2):122-32. doi: 10.1158/1541-7786.MCR-12-0569. Epub 2012 Dec 13. [PubMed:23239810]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involv...
Gene Name
IGF1R
Uniprot ID
P08069
Uniprot Name
Insulin-like growth factor 1 receptor
Molecular Weight
154791.73 Da
References
  1. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C: Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013 Feb;11(2):122-32. doi: 10.1158/1541-7786.MCR-12-0569. Epub 2012 Dec 13. [PubMed:23239810]
  2. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. Ceccon M, Mologni L, Bisson W, Scapozza L, Gambacorti-Passerini C: Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013 Feb;11(2):122-32. doi: 10.1158/1541-7786.MCR-12-0569. Epub 2012 Dec 13. [PubMed:23239810]
  2. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Binding
General Function
Receptor signaling protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (...
Gene Name
INSR
Uniprot ID
P06213
Uniprot Name
Insulin receptor
Molecular Weight
156331.465 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including...
Gene Name
MET
Uniprot ID
P08581
Uniprot Name
Hepatocyte growth factor receptor
Molecular Weight
155540.035 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mamma...
Gene Name
ERBB4
Uniprot ID
Q15303
Uniprot Name
Receptor tyrosine-protein kinase erbB-4
Molecular Weight
146806.865 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transmembrane signaling receptor activity
Specific Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
References
  1. FDA Reports [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
  2. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Markham A: Brigatinib: First Global Approval. Drugs. 2017 Jul;77(10):1131-1135. doi: 10.1007/s40265-017-0776-3. [PubMed:28597393]
  2. FDA Reports [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Reports [Link]

Drug created on October 20, 2016 15:46 / Updated on June 02, 2018 08:36