Identification

Name
Abemaciclib
Accession Number
DB12001
Type
Small Molecule
Groups
Approved
Description

Abemaciclib is an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) that are involved in the cell cycle and promotion of cancer cell growth in case of unregulated activity. On September 28, 2017, FDA granted approval of abemaciclib treatment under the market name Verzenio for the treatment of HR-positive and HER2-negative advanced or metastatic breast cancer that has progressed after unsuccessful endocrine therapy. It is either given alone in patients who has undergone endocrine therapy and chemotherapy after the metastasis of cancer, or in combination with Fulvestrant. Following oral treatment in patients with HR-positive, HER2-negative breast cancer, abemaciclib demonstrated increased progression-free survival rates and objective response rates. Abemaciclib has been used in trials studying the treatment of melanoma, lymphoma, neoplasm, solid tumor, and glioblastoma.

Structure
Thumb
Synonyms
  • LY2835219
External IDs
LY-2835219 / LY2835219
Product Ingredients
IngredientUNIICASInChI Key
Abemaciclib MesylateKKT462Q8071231930-82-7NCJPFQPEVDHJAZ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VerzenioTablet50 mg/1OralEli Lilly & Co. Ltd.2017-09-28Not applicableUs
VerzenioTablet150 mg/1OralEli Lilly & Co. Ltd.2017-09-28Not applicableUs
VerzenioTablet100 mg/1OralEli Lilly & Co. Ltd.2017-09-28Not applicableUs
VerzenioTablet200 mg/1OralEli Lilly & Co. Ltd.2017-09-28Not applicableUs
Categories
UNII
60UAB198HK
CAS number
1231929-97-7
Weight
Average: 506.606
Monoisotopic: 506.271799388
Chemical Formula
C27H32F2N8
InChI Key
UZWDCWONPYILKI-UHFFFAOYSA-N
InChI
InChI=1S/C27H32F2N8/c1-5-35-8-10-36(11-9-35)16-19-6-7-24(30-14-19)33-27-31-15-22(29)25(34-27)20-12-21(28)26-23(13-20)37(17(2)3)18(4)32-26/h6-7,12-15,17H,5,8-11,16H2,1-4H3,(H,30,31,33,34)
IUPAC Name
N-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl}-5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-1,3-benzodiazol-6-yl]pyrimidin-2-amine
SMILES
CCN1CCN(CC2=CC=C(NC3=NC=C(F)C(=N3)C3=CC(F)=C4N=C(C)N(C(C)C)C4=C3)N=C2)CC1

Pharmacology

Indication
  • Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.

  • Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Structured Indications
Pharmacodynamics

In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19.7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8.6 months after treatment [5]. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models [1].

In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval [FDA Label].

Mechanism of action

Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb [1, 2].

Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors [1]. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point [1]. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing [1].

Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells [1]. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6 [2].

TargetActionsOrganism
ACyclin-dependent kinase 4
inhibitor
Human
ACyclin-dependent kinase 6
inhibitor
Human
Absorption

The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg [2], but may range up to 24 hours [FDA Label]. The absolute bioavailability of the drug is reported to be 45% [FDA Label].

Volume of distribution

The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV) [FDA Label].

Protein binding

According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98% [4]. While abemaciclib demonstrated in vitro binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93.4%, 96.8% and 97.8%, respectively [FDA Label].

Metabolism

Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively [FDA Label].

Route of elimination

Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites [FDA Label].

Half life

The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV) [FDA Label].

Clearance

The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV) [FDA Label].

Toxicity

According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis [FDA Label].

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

Interactions

Drug Interactions
DrugInteractionDrug group
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Abemaciclib.Approved
AmiodaroneThe risk or severity of adverse effects can be increased when Amiodarone is combined with Abemaciclib.Approved, Investigational
AprepitantThe serum concentration of Abemaciclib can be increased when it is combined with Aprepitant.Approved, Investigational
AtazanavirThe risk or severity of adverse effects can be increased when Atazanavir is combined with Abemaciclib.Approved, Investigational
AtomoxetineThe metabolism of Abemaciclib can be decreased when combined with Atomoxetine.Approved
BoceprevirThe risk or severity of adverse effects can be increased when Boceprevir is combined with Abemaciclib.Approved, Withdrawn
BortezomibThe metabolism of Abemaciclib can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Abemaciclib can be decreased when it is combined with Bosentan.Approved, Investigational
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Abemaciclib.Approved
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Abemaciclib.Approved
CarbamazepineThe serum concentration of Abemaciclib can be decreased when it is combined with Carbamazepine.Approved, Investigational
CeritinibThe risk or severity of adverse effects can be increased when Ceritinib is combined with Abemaciclib.Approved
ClarithromycinThe risk or severity of adverse effects can be increased when Clarithromycin is combined with Abemaciclib.Approved
ClemastineThe metabolism of Abemaciclib can be decreased when combined with Clemastine.Approved
ClotrimazoleThe metabolism of Abemaciclib can be decreased when combined with Clotrimazole.Approved, Vet Approved
CobicistatThe risk or severity of adverse effects can be increased when Cobicistat is combined with Abemaciclib.Approved
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Abemaciclib.Approved
ConivaptanThe serum concentration of Abemaciclib can be increased when it is combined with Conivaptan.Approved, Investigational
CrizotinibThe metabolism of Abemaciclib can be decreased when combined with Crizotinib.Approved
CyclosporineThe metabolism of Abemaciclib can be decreased when combined with Cyclosporine.Approved, Investigational, Vet Approved
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Abemaciclib.Approved
DabrafenibThe serum concentration of Abemaciclib can be decreased when it is combined with Dabrafenib.Approved
DarunavirThe risk or severity of adverse effects can be increased when Darunavir is combined with Abemaciclib.Approved
DasatinibThe serum concentration of Abemaciclib can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Abemaciclib can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Abemaciclib can be decreased when combined with Delavirdine.Approved
DihydroergotamineThe metabolism of Abemaciclib can be decreased when combined with Dihydroergotamine.Approved
DiltiazemThe metabolism of Abemaciclib can be decreased when combined with Diltiazem.Approved
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Abemaciclib.Approved, Investigational
DoxycyclineThe metabolism of Abemaciclib can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe metabolism of Abemaciclib can be decreased when combined with Dronedarone.Approved
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Abemaciclib.Approved
EltrombopagThe serum concentration of Abemaciclib can be increased when it is combined with Eltrombopag.Approved
ErythromycinThe metabolism of Abemaciclib can be decreased when combined with Erythromycin.Approved, Vet Approved
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Abemaciclib.Approved
FluconazoleThe metabolism of Abemaciclib can be decreased when combined with Fluconazole.Approved
FluvoxamineThe metabolism of Abemaciclib can be decreased when combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Abemaciclib can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Abemaciclib can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe serum concentration of Abemaciclib can be decreased when it is combined with Fosphenytoin.Approved
Fusidic AcidThe serum concentration of Abemaciclib can be increased when it is combined with Fusidic Acid.Approved
IdelalisibThe risk or severity of adverse effects can be increased when Idelalisib is combined with Abemaciclib.Approved
ImatinibThe metabolism of Abemaciclib can be decreased when combined with Imatinib.Approved
IndinavirThe risk or severity of adverse effects can be increased when Indinavir is combined with Abemaciclib.Approved
IsavuconazoniumThe metabolism of Abemaciclib can be decreased when combined with Isavuconazonium.Approved, Investigational
IsradipineThe metabolism of Abemaciclib can be decreased when combined with Isradipine.Approved
ItraconazoleThe risk or severity of adverse effects can be increased when Itraconazole is combined with Abemaciclib.Approved, Investigational
IvacaftorThe serum concentration of Abemaciclib can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe serum concentration of Abemaciclib can be increased when it is combined with Ketoconazole.Approved, Investigational
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Abemaciclib.Approved
LopinavirThe risk or severity of adverse effects can be increased when Lopinavir is combined with Abemaciclib.Approved
LovastatinThe metabolism of Abemaciclib can be decreased when combined with Lovastatin.Approved, Investigational
LuliconazoleThe serum concentration of Abemaciclib can be increased when it is combined with Luliconazole.Approved
MidostaurinThe serum concentration of Abemaciclib can be decreased when it is combined with Midostaurin.Approved
MifepristoneThe serum concentration of Abemaciclib can be increased when it is combined with Mifepristone.Approved, Investigational
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Abemaciclib.Approved
NefazodoneThe risk or severity of adverse effects can be increased when Nefazodone is combined with Abemaciclib.Approved, Withdrawn
NelfinavirThe risk or severity of adverse effects can be increased when Nelfinavir is combined with Abemaciclib.Approved
NetupitantThe serum concentration of Abemaciclib can be increased when it is combined with Netupitant.Approved
NevirapineThe serum concentration of Abemaciclib can be decreased when it is combined with Nevirapine.Approved
NilotinibThe metabolism of Abemaciclib can be decreased when combined with Nilotinib.Approved, Investigational
OlaparibThe metabolism of Abemaciclib can be decreased when combined with Olaparib.Approved
OsimertinibThe serum concentration of Abemaciclib can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Abemaciclib can be increased when it is combined with Palbociclib.Approved
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Abemaciclib.Approved
PentobarbitalThe serum concentration of Abemaciclib can be decreased when it is combined with Pentobarbital.Approved, Vet Approved
PhenobarbitalThe serum concentration of Abemaciclib can be decreased when it is combined with Phenobarbital.Approved
PhenytoinThe serum concentration of Abemaciclib can be decreased when it is combined with Phenytoin.Approved, Vet Approved
PosaconazoleThe risk or severity of adverse effects can be increased when Posaconazole is combined with Abemaciclib.Approved, Investigational, Vet Approved
PrimidoneThe serum concentration of Abemaciclib can be decreased when it is combined with Primidone.Approved, Vet Approved
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Abemaciclib.Approved
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Abemaciclib.Approved, Investigational
RifabutinThe serum concentration of Abemaciclib can be decreased when it is combined with Rifabutin.Approved
RifampicinThe serum concentration of Abemaciclib can be decreased when it is combined with Rifampicin.Approved
RifapentineThe serum concentration of Abemaciclib can be decreased when it is combined with Rifapentine.Approved
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Abemaciclib.Approved, Investigational
RolapitantThe serum concentration of Abemaciclib can be increased when it is combined with Rolapitant.Approved
SaquinavirThe risk or severity of adverse effects can be increased when Saquinavir is combined with Abemaciclib.Approved, Investigational
SildenafilThe metabolism of Abemaciclib can be decreased when combined with Sildenafil.Approved, Investigational
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Abemaciclib.Approved
SiltuximabThe serum concentration of Abemaciclib can be decreased when it is combined with Siltuximab.Approved
SimeprevirThe serum concentration of Abemaciclib can be increased when it is combined with Simeprevir.Approved
StiripentolThe risk or severity of adverse effects can be increased when Stiripentol is combined with Abemaciclib.Approved
SulfisoxazoleThe metabolism of Abemaciclib can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TelaprevirThe risk or severity of adverse effects can be increased when Telaprevir is combined with Abemaciclib.Approved, Withdrawn
TelithromycinThe risk or severity of adverse effects can be increased when Telithromycin is combined with Abemaciclib.Approved
TeriflunomideThe serum concentration of Abemaciclib can be increased when it is combined with Teriflunomide.Approved
TiclopidineThe metabolism of Abemaciclib can be decreased when combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Abemaciclib can be decreased when it is combined with Tocilizumab.Approved
VenlafaxineThe metabolism of Abemaciclib can be decreased when combined with Venlafaxine.Approved
VerapamilThe metabolism of Abemaciclib can be decreased when combined with Verapamil.Approved
VincristineThe serum concentration of Vincristine can be increased when it is combined with Abemaciclib.Approved, Investigational
VoriconazoleThe risk or severity of adverse effects can be increased when Voriconazole is combined with Abemaciclib.Approved, Investigational
ZiprasidoneThe metabolism of Abemaciclib can be decreased when combined with Ziprasidone.Approved
Food Interactions
Not Available

References

General References
  1. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A: Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37. doi: 10.1007/s10637-014-0120-7. Epub 2014 Jun 13. [PubMed:24919854]
  2. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, Flaherty KT, Wen PY, Shapiro GI: Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov. 2016 Jul;6(7):740-53. doi: 10.1158/2159-8290.CD-16-0095. Epub 2016 May 23. [PubMed:27217383]
  3. Tate SC, Sykes AK, Kulanthaivel P, Chan EM, Turner PK, Cronier DM: A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients. Clin Pharmacokinet. 2017 May 24. doi: 10.1007/s40262-017-0559-8. [PubMed:28540640]
  4. Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, Gelbert LM, Shannon HE, Sanchez-Martinez C, De Dios A: Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft. Drug Metab Dispos. 2015 Sep;43(9):1360-71. doi: 10.1124/dmd.114.062745. Epub 2015 Jul 6. [PubMed:26149830]
  5. FDA approves new treatment for certain advanced or metastatic breast cancers [Link]
External Links
PubChem Compound
46220502
PubChem Substance
347828320
ChemSpider
29340700
BindingDB
50110183
ChEMBL
CHEMBL3301610
PharmGKB
PA166153471
HET
6ZV
PDB Entries
5l2s
FDA label
Download (325 KB)
MSDS
Download (23.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCancer, Advanced1
1Active Not RecruitingTreatmentCancer, Advanced / Colorectal Cancers / Mantle Cell Lymphoma (MCL)1
1Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Neoplasms Metastasis1
1Active Not RecruitingTreatmentMalignant Lymphomas / Neoplasms Metastasis1
1CompletedBasic ScienceHealthy Volunteers8
1CompletedBasic ScienceHealthy Volunteers / Hepatic Insufficiency1
1CompletedBasic ScienceNeoplasms / Neoplasms Metastasis1
1RecruitingBasic ScienceNeoplasms Metastasis1
1RecruitingTreatmentBrain Tumor, Recurrent / Diffuse Intrinsic Pontine Glioma (DIPG) / Ewing Sarcoma, Recurrent, Refractory / Neuroblastoma, Recurrent, Refractory / Osteosarcoma, Recurrent, Refractory / Rhabdoid Tumor, Recurrent, Refractory / Rhabdomyosarcoma, Recurrent, Refractory / Solid Tumor, Recurrent1
1RecruitingTreatmentBreast Cancer (HR+HER2-) / Cutaneous Melanoma / Malignant Neoplasm of Pancreas / Microsatellite Instability-High (MSI-H) Solid Tumors / Tumors, Solid1
1RecruitingTreatmentCancer, Advanced / Colorectal Cancers / Metastatic Melanoma / Metastatic Non-Small Cell Lung Cancer / Metastatic Pancreatic Ductal Adenocarcinoma1
1RecruitingTreatmentCancer, Advanced / Lung Cancer Non-Small Cell Cancer (NSCLC) / Mesothelioma, Malignant / Metastatic Breast Cancer (MBC) / Metastatic Cancers / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentCancer, Advanced / Metastatic Cancers1
1RecruitingTreatmentCancer, Breast / Cholangiocarcinomas / Malignant Neoplasm of Colon / Soft Tissue Sarcoma (STS) / Tumors, Solid1
1RecruitingTreatmentCancer, Breast / Lung Cancer Non-Small Cell Cancer (NSCLC)1
1RecruitingTreatmentNeoplasms, Breast1
1RecruitingTreatmentNeoplasms / Neoplasms, Breast1
1RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2Active Not RecruitingTreatmentAdvanced Non-Small Cell Lung Cancer1
2Active Not RecruitingTreatmentMantle Cell Lymphoma (MCL)1
2Active Not RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2Active Not RecruitingTreatmentPancreatic Ductal Adenocarcinoma1
2CompletedTreatmentCancer, Breast / Early-Stage Breast Carcinoma / Hormone Receptor Positive Tumor1
2Not Yet RecruitingTreatmentAdenocarcinoma Of Esophagus / Cholangiocarcinomas / Endometrial Cancers / Esophagus SCC / Urothelial/Bladder Cancer, Nos1
2Not Yet RecruitingTreatmentCancer, Advanced / Head and Neck Carcinoma / Metastatic Cancers1
2RecruitingPreventionHNSCC / Neoplasms, Head and Neck2
2RecruitingTreatmentCancer, Breast2
2RecruitingTreatmentCancer, Breast / Lung Cancer Non-Small Cell Cancer (NSCLC) / Melanoma / Metastatic Brain Tumors1
2RecruitingTreatmentCancers1
2RecruitingTreatmentGlioblastomas2
2RecruitingTreatmentHER-2 Positive Breast Cancer / Hormone Receptor Positive Tumor1
2RecruitingTreatmentLiposarcomas, Dedifferentiated / Sarcomas1
2RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2RecruitingTreatmentNeoplasms, Brain1
3Active Not RecruitingTreatmentCancer, Breast1
3Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
3Active Not RecruitingTreatmentNeoplasms, Breast1
3RecruitingTreatmentCancer, Breast2
Not AvailableApproved for MarketingNot AvailableMetastatic Breast Cancer (MBC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg/1
TabletOral150 mg/1
TabletOral200 mg/1
TabletOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7855211No2009-12-152029-12-15Us

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0159 mg/mLALOGPS
logP4.25ALOGPS
logP4.42ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)10.27ChemAxon
pKa (Strongest Basic)7.94ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area75 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity141.26 m3·mol-1ChemAxon
Polarizability54.75 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 benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzimidazoles
Sub Class
Not Available
Direct Parent
Benzimidazoles
Alternative Parents
N-alkylpiperazines / Halopyrimidines / Aralkylamines / Aminopyrimidines and derivatives / Aminopyridines and derivatives / N-substituted imidazoles / Imidolactams / Benzenoids / Aryl fluorides / Heteroaromatic compounds
show 4 more
Substituents
Benzimidazole / Aminopyridine / Aminopyrimidine / Halopyrimidine / Aralkylamine / N-alkylpiperazine / Aryl fluoride / Aryl halide / 1,4-diazinane / N-substituted imidazole
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Cyclin-dependent protein serine/threonine kinase regulator activity
Specific Function
Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S tra...
Gene Name
CDK4
Uniprot ID
P11802
Uniprot Name
Cyclin-dependent kinase 4
Molecular Weight
33729.55 Da
References
  1. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A: Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37. doi: 10.1007/s10637-014-0120-7. Epub 2014 Jun 13. [PubMed:24919854]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Cyclin-dependent protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during int...
Gene Name
CDK6
Uniprot ID
Q00534
Uniprot Name
Cyclin-dependent kinase 6
Molecular Weight
36938.025 Da
References
  1. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A: Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37. doi: 10.1007/s10637-014-0120-7. Epub 2014 Jun 13. [PubMed:24919854]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, Flaherty KT, Wen PY, Shapiro GI: Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov. 2016 Jul;6(7):740-53. doi: 10.1158/2159-8290.CD-16-0095. Epub 2016 May 23. [PubMed:27217383]
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. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, Flaherty KT, Wen PY, Shapiro GI: Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov. 2016 Jul;6(7):740-53. doi: 10.1158/2159-8290.CD-16-0095. Epub 2016 May 23. [PubMed:27217383]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Phospholipid binding
Specific Function
Not Available
Gene Name
OTC
Uniprot ID
P00480
Uniprot Name
Ornithine carbamoyltransferase, mitochondrial
Molecular Weight
39934.775 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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

Drug created on October 20, 2016 15:09 / Updated on December 01, 2017 17:31