RAF-265

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H16F6N6O
Molecular Weight	518.4139
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1C(NC2=CC=C(C=C2)C(F)(F)F)=NC3=CC(OC4=CC(=NC=C4)C5=NC=C(N5)C(F)(F)F)=CC=C13

InChI

InChIKey=YABJJWZLRMPFSI-UHFFFAOYSA-N

InChI=1S/C24H16F6N6O/c1-36-19-7-6-15(10-17(19)34-22(36)33-14-4-2-13(3-5-14)23(25,26)27)37-16-8-9-31-18(11-16)21-32-12-20(35-21)24(28,29)30/h2-12H,1H3,(H,32,35)(H,33,34)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23617957 | https://www.ncbi.nlm.nih.gov/pubmed/28719152 | https://www.ncbi.nlm.nih.gov/pubmed/26396681 | https://www.ncbi.nlm.nih.gov/pubmed/26081844

CHIR-265 (RAF265) is a potent selective orally active small molecule Raf-kinase inhibitor with anti‐angiogenic activity through inhibition of vascular endothelial growth factor type 2 (VEGFR‐2) in preclinical models. CHIR-265 effectively block phosphorylation of Raf's downstream substrates MEK and ERK in cells and also kill melanoma and colorectal cancer cell lines harboring B-Raf mutations independent of PTEN mutation status. Raf kinase inhibition by CHIR-265 in mutant B-Raf melanoma cell lines causes cell cycle arrest and induces apoptosis, mimicking the effect of Raf RNAi in these cells. CHIR-265 also potently inhibits the phosphorylation of VEGFR2 and proliferation of VEGF-stimulated hMVEC.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase B-raf 21 Target ID: CHEMBL5145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26396681	Inhibitor 8504	20.0 nM [IC50]
Vascular endothelial growth factor receptor 11 Target ID: CHEMBL2095227 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26396681	Inhibitor 8504	20.0 nM [IC50]
Mast/stem cell growth factor receptor Kit 6 Target ID: P10721 Gene ID: 3815.0 Gene Symbol: KIT Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26396681	Inhibitor 8504	20.0 nM [IC50]
Platelet-derived growth factor receptor beta 56 Target ID: P09619 Gene ID: 5159.0 Gene Symbol: PDGFRB Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26396681	Inhibitor 8504	6.0 nM [IC50]

C_max

Value	Dose	Analyte	Population
0.14 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.15 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.26 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	36 mg single, oral dose: 36 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.54 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	72 mg single, oral dose: 72 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.06 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	144 mg single, oral dose: 144 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.31 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg single, oral dose: 288 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.68 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	403 mg single, oral dose: 403 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.13 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	10 mg 1 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.12 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.2 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	36 mg 1 times / day steady-state, oral dose: 36 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.42 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	72 mg 1 times / day steady-state, oral dose: 72 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.85 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	144 mg 1 times / day steady-state, oral dose: 144 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.65 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg 1 times / day steady-state, oral dose: 288 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.65 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	403 mg 1 times / day steady-state, oral dose: 403 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.31 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg 1 times / day multiple, oral dose: 288 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RAF-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1.65 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	48 mg 1 times / day steady-state, oral dose: 48 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RAF-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
6.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.77 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	36 mg single, oral dose: 36 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
22.6 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	72 mg single, oral dose: 72 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
51.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	144 mg single, oral dose: 144 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
99.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg single, oral dose: 288 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
137 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	403 mg single, oral dose: 403 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.67 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	10 mg 1 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.3 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.15 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	36 mg 1 times / day steady-state, oral dose: 36 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.59 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	72 mg 1 times / day steady-state, oral dose: 72 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
16.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	144 mg 1 times / day steady-state, oral dose: 144 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
28.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg 1 times / day steady-state, oral dose: 288 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
46.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	403 mg 1 times / day steady-state, oral dose: 403 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
99.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg 1 times / day multiple, oral dose: 288 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RAF-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
28.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	48 mg 1 times / day steady-state, oral dose: 48 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RAF-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
287 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
209 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	20 mg single, oral dose: 20 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
127 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	36 mg single, oral dose: 36 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
174 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	72 mg single, oral dose: 72 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
182 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	144 mg single, oral dose: 144 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
183 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg single, oral dose: 288 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
294 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	403 mg single, oral dose: 403 mg route of administration: Oral experiment type: SINGLE co-administered:	CHIR-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
183 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	288 mg 1 times / day multiple, oral dose: 288 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RAF-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
183 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28719152/	48 mg 1 times / day steady-state, oral dose: 48 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RAF-265 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% EXPERIMENT https://pubs.acs.org/doi/full/10.1021/ml500526p	single, unknown		CHIR-265 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

PubMed

Title	Date	PubMed
Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination.	2010 Feb	20124452
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378

Patents

Sample Use Guides

In Vivo Use Guide

MTD was 48 mg once daily

Route of Administration: Oral

Name

Type

Language

NVP-RAF265

Preferred Name

English

RAF-265

Common Name

English

1-METHYL-5-((2-(5-(TRIFLUOROMETHYL)-1H-IMIDAZOL-2-YL)-4-PYRIDINYL)OXY)-N-(4-(TRIFLUOROMETHYL)PHENYL)-1H-BENZIMIDAZOL-2-AMINE

Systematic Name

English

RAF265

Code

English

RAF 265 [WHO-DD]

Common Name

English

CHIR-265

Code

English

Code System Code Type Description

EPA CompTox

DTXSID601025871