Tovorafenib

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H12Cl2F3N7O2S
Molecular Weight	506.289
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H](NC(=O)C1=C(Cl)C(N)=NC=N1)C2=NC=C(S2)C(=O)NC3=NC=C(Cl)C(=C3)C(F)(F)F

InChI

InChIKey=VWMJHAFYPMOMGF-ZCFIWIBFSA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.sunesis.com/data-pdf/partnered/BIIB024-AACR-201011.pdf
Curator's Comment: Description was created based on several sources, including https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=710688

BIIB-024, also known as MLN2480, and AMG 2112819, is an oral, selective pan-Raf kinase inhibitor. The Raf kinases (A-Raf, B-Raf and C-Raf) are key regulators of cell proliferation and survival within the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is frequently disregulated in human cancers, often via activating mutations of Ras or Raf. BIIB-024 inhibits MAPK pathway signaling in BRAF mutant and some RAS mutant preclinical cancer models at concentrations that are tolerated in vivo. BIIB-024 is most potent in BRAF mutant melanoma models but also has single agent activity in some RAS mutant models. The combination of BIIB-024 with TAK-733 inhibits the growth of a broader range of RAS mutant tumor models than single agent BIIB-024, including primary human tumor xenograft models of melanoma and CRC. BIIB-024 is in phase I clinical trials for the treatment of malignant melanoma and solid tumours.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase B-raf 21 Target ID: CHEMBL5145 Sources: http://www.sunesis.com/data-pdf/partnered/BIIB024-AACR-201011.pdf	Inhibitor 8504	10.1 nM [IC50]
Serine/threonine-protein kinase RAF 11 Target ID: CHEMBL1906 Sources: http://www.sunesis.com/data-pdf/partnered/BIIB024-AACR-201011.pdf	Inhibitor 8504	0.7 nM [IC50]
Tyrosine-protein kinase FRK 1 Target ID: CHEMBL4223 Sources: http://www.sunesis.com/data-pdf/partnered/BIIB024-AACR-201011.pdf	Inhibitor 8504	1.0 nM [IC50]
Tyrosine-protein kinase ABL2 1 Target ID: CHEMBL4014 Sources: http://www.sunesis.com/data-pdf/partnered/BIIB024-AACR-201011.pdf	Inhibitor 8504	3.0 nM [IC50]
Tyrosine-protein kinase LCK 14 Target ID: CHEMBL258 Sources: http://www.sunesis.com/data-pdf/partnered/BIIB024-AACR-201011.pdf	Inhibitor 8504	16.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT01425008	Primary		Phase I 438	Unknown Approved Use Unknown
Solid tumors 147 Sources: https://clinicaltrials.gov/ct2/show/NCT01425008	Primary		Phase I 438	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
3140 ng/mL CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	400 mg 1 times / week multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5650 ng/mL CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	600 mg 1 times / week multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
6460 ng/mL CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	800 mg 1 times / week multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
193000 ng × h/mL CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	400 mg 1 times / week multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
330000 ng × h/mL CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	600 mg 1 times / week multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
473000 ng × h/mL CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	800 mg 1 times / week multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
184534.4 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
278247.9 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
431723.3 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4799.7 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	20 mg 1 times / 2 days multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
11019.7 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	40 mg 1 times / 2 days multiple, oral dose: 40 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
30562.8 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	80 mg 1 times / 2 days multiple, oral dose: 80 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
36061.9 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	135 mg 1 times / 2 days multiple, oral dose: 135 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
50946.5 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	200 mg 1 times / 2 days multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
78993.3 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	280 mg 1 times / 2 days multiple, oral dose: 280 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
66799.2 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	200 mg 1 times / 2 days multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
53522.2 ng × h/mL CLINICAL TRIAL https://clinicaltrials.gov/study/NCT01425008?tab=results	200 mg 1 times / 2 days multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
52 h CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	400 mg 1 times / week multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
70.5 h CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	600 mg 1 times / week multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
68.1 h CLINICAL TRIAL https://link.springer.com/article/10.1007/s00280-023-04544-5	800 mg 1 times / week multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	TOVORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY34302	https://www.001chemical.com/chem/search?q=DY34302
1PlusChem LLC	1P008TYY	https://www.1pchem.com/search?query=1P008TYY
AK Scientific	3301AH	https://aksci.com/item_detail.php?cat=3301AH
Angene	AGN-PC-0WH9XN	http://www.angenechemical.com/productshow/AGN-PC-0WH9XN.html
AstaTech	P13369	http://astatechinc.com/CPSResult.php?CRNO=P13369
BLD Pharm	BD287791	http://www.bldpharm.com/search/Search.html?keyword=BD287791
BOC Sciences	1096708-71-2	http://www.bocsci.com/description.asp?cas=1096708-71-2
Cayman Chemical	19675	http://www.caymanchem.com/app/template/Product.vm/catalog/19675
ChemShuttle	131674	https://www.chemshuttle.com/catalogsearch/result/?q=131674
Combi-Blocks	QM-8197	http://www.combi-blocks.com/cgi-bin/find.cgi?QM-8197
eMolecules	275055524	https://orderbb.emolecules.com/search/#?query=275055524
eMolecules	300753176	https://orderbb.emolecules.com/search/#?query=300753176
eMolecules	44811456	https://orderbb.emolecules.com/search/#?query=44811456
eNovation Chemicals	D548311	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D548311&searchbtn.x=0&searchbtn.y=0
KeyOrganics	AS-75178	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-75178
Matrix Scientific	152566	http://www.matrixscientific.com/152566.html
mcule	MCULE-7629045546	https://mcule.com/MCULE-7629045546/
mcule	MCULE-8218884403	https://mcule.com/MCULE-8218884403/
MedChem Express	HY-15246	https://www.medchemexpress.com/search.html?q=HY-15246&ft=&fa=&fp=
Molcore	MC34302	http://www.molcore.com/CatMC34302.html
Molnova	M17143	https://www.molnova.com/en/serch-list.html?keywords=M17143
MolPort	MolPort-039-139-511	https://www.molport.com/shop/molecule-link/MolPort-039-139-511
MolPort	MolPort-046-702-045	https://www.molport.com/shop/molecule-link/MolPort-046-702-045
MuseChem	I000407	https://www.musechem.com/product/I000407.html
Selleck Chemicals	S7121	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7121
ShangHai Biochempartner	BCP13797	http://www.biochempartner.com/search_BCP13797
TargetMol	T6895	https://www.targetmol.com/search?keyword=T6895

Patents

Sample Use Guides

In Vivo Use Guide

100 mg, tablets, orally, once on protocol specified days of a 28-day Cycle for up to 12 Cycles

Route of Administration: Oral

In Vitro Use Guide

BIIB-024 inhibits a small subset of kinases in a similar range as Raf kinases (IC50 1-50 nM)

Name

Type

Language

BIIB024

Preferred Name

English

Tovorafenib

Official Name

English

DAY-101

Code

English

tovorafenib [INN]

Common Name

English

TOVORAFENIB [USAN]

Common Name

English

4-Pyrimidinecarboxamide, 6-amino-5-chloro-N-[(1R)-1-[5-[[[5-chloro-4-(trifluoromethyl)-2-pyridinyl]amino]carbonyl]-2-thiazolyl]ethyl]-

Systematic Name

English

DAY101

Code

English

OJEMDA

Brand Name

English

MLN-2480

Common Name

English

Tovorafenib [WHO-DD]

Common Name

English

MLN2480

Common Name

English

6-amino-5-chloro-N-{(1R)-1-(5-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}thiazol-2-yl)ethyl}pyrimidine-4-carboxamide

Systematic Name

English

TAK-580

Code

English

BIIB-024

Code

English

MLN-2480

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

410813