NAV

Tovorafenib

Identification

Summary

Tovorafenib is a type II RAF inhibitor used to treat pediatric low-grade glioma with BRAF gene mutations.

Generic Name
Tovorafenib
DrugBank Accession Number
DB15266
Background

Tovorafenib is a selective type II RAF kinase inhibitor with anti-tumour activity.1 It was granted accelerated approval by the FDA, making it the first FDA approval of a systemic therapy for the treatment of pediatric low-grade glioma, with BRAF rearrangements.5 BRAF oncogenic mutations in cancers drive dysregulated cell growth, proliferation, and differentiation.2 Tovorafenib inhibits BRAF and blocks dysregulated signalling pathways related to cancer cell growth and survival.5

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 506.29
Monoisotopic: 505.0102337
Chemical Formula
C17H12Cl2F3N7O2S
Synonyms
  • 4-Pyrimidinecarboxamide, 6-amino-5-chloro-N-[(1R)-1-[5-[[[5-chloro-4-(trifluoromethyl)-2-pyridinyl]amino]carbonyl]-2-thiazolyl]ethyl]-
  • 6-Amino-5-chloro-N-((1R)-1-(5-(((5-chloro-4-(trifluoromethyl)-2-pyridinyl)amino)carbonyl)-2-thiazolyl)ethyl)-4-pyrimidinecarboxamide
  • 6-amino-5-chloro-N-[1R)-1-[5-[[[5-hloro-4-(trifluoromethyl)-2pyridinyl]amino]carbonyl]-2-thiazoyl]ethyl]-4-pyrimdinecarboxamide
External IDs
  • AMG 2112819
  • BIIB 024
  • BIIB-024
  • BIIB024
  • DAY 101
  • DAY-101
  • DAY101
  • MLN 2480
  • MLN-2480
  • MLN2480
  • TAK 580
  • TAK-580
  • TAK580
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Pharmacology

Indication

Tovorafenib is indicated for the treatment of patients six months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofRefractory pediatric low-grade gliomas••••••••••••••••••••••••• •••• •••••••••••••••••••••••• ••••••
Treatment ofRefractory pediatric low-grade gliomas••••••••••••••••••••••••• •••• ••••••••••••••••• ••••••
Treatment ofRefractory pediatric low-grade gliomas•••••••••••••••••••••••••••••••• ••••••
Treatment ofRelapsed pediatric low-grade gliomas••••••••••••••••••••••••• •••• •••••••••••••••••••••••• ••••••
Treatment ofRelapsed pediatric low-grade gliomas••••••••••••••••••••••••• •••• ••••••••••••••••• ••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Tovorafenib is an anticancer agent with antitumour activity.1 Exposure to tovorafenib is associated with a reduction in height-for-age z-scores in pediatric patients. Reduced height-for-age risk persists during treatment with tovorafenib. Higher drug exposure is associated with an increased risk of skin rash, elevated liver enzymes (AST and ALT), and elevated creatinine phosphokinase.4

Mechanism of action

Pediatric low-grade glioma, the most common childhood central nervous system (CNS) tumour, is often associated with BRAF genomic alterations, such as BRAF fusion or rearrangement.1,2 The BRAF kinase family is activated by RAS to phosphorylate MEK1/2, which phosphorylates ERK1/2 and promotes downstream signalling cascades that regulate multiple cellular processes, such as cell growth, proliferation, and differentiation.2 Oncogenic mutations in BRAF lead to an aberrant and hyperactivated RAS-RAF-MEK-ERK pathway, also known as the mitogen-activated protein kinase (MAPK) signalling pathway.3

Several RAF kinase inhibitors have been developed to treat cancers with BRAF mutations. These RAF inhibitors have been categorized into different "types" depending on their selectivity to a BRAF isoform and binding modes.2 Tovorafenib is a Type II RAF kinase inhibitor. RAF has a conserved three-residue segment (Asp-Phe-Gly) located at the N-terminus of the kinase activation loop called a DFG motif. In a state called a “DGF-out” conformation, the DFG motif is flipped in a way that reorients the phenylalanine residue, leaving a vacant site in which the drug can extend from the ATP site to insert a hydrophobic group.2 Tovorafenib is active against mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases.3,4 Tovorafenib exhibited antitumor activity in cultured cells and xenograft tumour models harbouring BRAF V600E and V600D mutations, and in a xenograft model harbouring a BRAF fusion.4 Tovorafenib is not reported to induce paradoxical activation of the MAPK pathway.1

TargetActionsOrganism
ARAF proto-oncogene serine/threonine-protein kinase
inhibitor
Humans
Absorption

Tovorafenib steady-state maximum concentration (Cmax) is 6.9 µg/mL (23%) and the area under the concentration-time curve (AUC) is 508 µg*h/mL (31%). The time to reach a steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. Tovorafenib median (minimum, maximum) time to achieve peak plasma concentration (Tmax) is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.4

No clinically significant differences in tovorafenib Cmax and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the Tmax was delayed to 6.5 hours.4

Volume of distribution

Tovorafenib apparent volume of distribution is 60 L/m2 (23%).4 It crosses the blood-brain barrier.1

Protein binding

Tovorafenib is 97.5% bound to human plasma proteins in vitro.4

Metabolism

Tovorafenib is primarily metabolized by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9, and CYP2C19 metabolize tovorafenib to a minor extent.4

Route of elimination

Following a single oral dose of radiolabeled tovorafenib, 65% of the total radiolabeled dose was recovered in the feces (8.6% unchanged) and 27% of the dose was recovered in the urine (0.2% unchanged).4

Half-life

Tovorafenib terminal half-life is approximately 56 hours (33%).4

Clearance

The apparent clearance is 0.7 L/h/m2 (31%).4

Adverse Effects
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Toxicity

There is limited information regarding the acute toxicity and overdosage of tovorafenib.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Tovorafenib.
AbirateroneThe metabolism of Tovorafenib can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Tovorafenib.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Tovorafenib.
AlectinibThe metabolism of Alectinib can be increased when combined with Tovorafenib.
Food Interactions
  • Take with or without food. Food may delay Tmax, but has negligible effects on drug exposure.

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
ZN90E4027M
CAS number
1096708-71-2
InChI Key
VWMJHAFYPMOMGF-ZCFIWIBFSA-N
InChI
InChI=1S/C17H12Cl2F3N7O2S/c1-6(28-15(31)12-11(19)13(23)27-5-26-12)16-25-4-9(32-16)14(30)29-10-2-7(17(20,21)22)8(18)3-24-10/h2-6H,1H3,(H,28,31)(H2,23,26,27)(H,24,29,30)/t6-/m1/s1
IUPAC Name
6-amino-5-chloro-N-[(1R)-1-(5-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}-1,3-thiazol-2-yl)ethyl]pyrimidine-4-carboxamide
SMILES
C[C@@H](NC(=O)C1=C(Cl)C(N)=NC=N1)C1=NC=C(S1)C(=O)NC1=NC=C(Cl)C(=C1)C(F)(F)F

References

General References
  1. Kilburn LB, Khuong-Quang DA, Hansford JR, Landi D, van der Lugt J, Leary SES, Driever PH, Bailey S, Perreault S, McCowage G, Waanders AJ, Ziegler DS, Witt O, Baxter PA, Kang HJ, Hassall TE, Han JW, Hargrave D, Franson AT, Yalon Oren M, Toledano H, Larouche V, Kline C, Abdelbaki MS, Jabado N, Gottardo NG, Gerber NU, Whipple NS, Segal D, Chi SN, Oren L, Tan EEK, Mueller S, Cornelio I, McLeod L, Zhao X, Walter A, Da Costa D, Manley P, Blackman SC, Packer RJ, Nysom K: The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med. 2024 Jan;30(1):207-217. doi: 10.1038/s41591-023-02668-y. Epub 2023 Nov 17. [Article]
  2. Tkacik E, Li K, Gonzalez-Del Pino G, Ha BH, Vinals J, Park E, Beyett TS, Eck MJ: Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib. J Biol Chem. 2023 May;299(5):104634. doi: 10.1016/j.jbc.2023.104634. Epub 2023 Mar 22. [Article]
  3. van Tilburg CM, Kilburn LB, Perreault S, Schmidt R, Azizi AA, Cruz-Martinez O, Zapotocky M, Scheinemann K, Meeteren AYNS, Sehested A, Opocher E, Driever PH, Avula S, Ziegler DS, Capper D, Koch A, Sahm F, Qiu J, Tsao LP, Blackman SC, Manley P, Milde T, Witt R, Jones DTW, Hargrave D, Witt O: LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration. BMC Cancer. 2024 Jan 30;24(1):147. doi: 10.1186/s12885-024-11820-x. [Article]
  4. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]
  5. FDA: FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma [Link]
ChemSpider
28637796
BindingDB
209864
ChEBI
167672
ChEMBL
CHEMBL3348923
ZINC
ZINC000043202464
PDBe Ligand
QOP
Wikipedia
Tovorafenib
PDB Entries
6v34 / 8f7o

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentLow-Grade Glioma1
2Not Yet RecruitingTreatmentRecurrent Langerhans Cell Histiocytosis / Refractory Langerhans cell histiocytosis1
2RecruitingTreatmentAdvanced Solid Tumors / Low-Grade Glioma1
2RecruitingTreatmentChildhood Craniopharyngioma / Craniopharyngioma / Recurrent Craniopharyngioma1
2RecruitingTreatmentRecurrent Langerhans Cell Histiocytosis / Refractory Langerhans cell histiocytosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)585.3https://file.medchemexpress.com/batch_PDF/HY-15246/Tovorafenib-SDS-MedChemExpress.pdf
water solubility<1 mg/mLhttps://www.selleckchem.com/msds/MSDS_S7121.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00194 mg/mLALOGPS
logP3.15ALOGPS
logP2.99Chemaxon
logS-5.4ALOGPS
pKa (Strongest Acidic)10.29Chemaxon
pKa (Strongest Basic)2.29Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area135.78 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity114.04 m3·mol-1Chemaxon
Polarizability43.95 Å3Chemaxon
Number of Rings3Chemaxon
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/MSsplash10-0a4i-0001090000-34241afb0209b69184e6
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-052r-0105900000-52e95756cc87ed8cdb37
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udl-3811910000-012b342580044ad59a51
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4j-0900040000-ee2ec572b77aa05df578
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-000x-9511000000-c6d9b1e3adc3168dc157
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a59-0955300000-e7da53a0498035da6048
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. RAF proto-oncogene serine/threonine-protein kinase
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determin...
Gene Name
RAF1
Uniprot ID
P04049
Uniprot Name
RAF proto-oncogene serine/threonine-protein kinase
Molecular Weight
73051.025 Da
References
  1. Tkacik E, Li K, Gonzalez-Del Pino G, Ha BH, Vinals J, Park E, Beyett TS, Eck MJ: Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib. J Biol Chem. 2023 May;299(5):104634. doi: 10.1016/j.jbc.2023.104634. Epub 2023 Mar 22. [Article]
  2. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]

Enzymes

Details1. Cytochrome P450 2C8
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
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. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]
Details2. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
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. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]
Details3. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]
Details4. Cytochrome P450 2C19
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]
Details5. Cytochrome P450 1A2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]
Details6. Cytochrome P450 2B6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
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
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]

Transporters

Details1. ATP-binding cassette sub-family G member 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
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 Approved Drug Products: OJEMDA (tovorafenib) suspension and tablets, for oral use [Link]

Drug created at May 20, 2019 15:06 / Updated at May 01, 2024 20:30