CHIR-265 | CAS#927880-90-8 | VEGFR-2 inhibitor

MedKoo Cat#: 200770 | Name: RAF-265

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

RAF-265, also known as CHIR-265, is an orally bioavailable small molecule with potential antineoplastic activity.

Chemical Structure

RAF-265

CAS#927880-90-8

Theoretical Analysis

MedKoo Cat#: 200770

Name: RAF-265

CAS#: 927880-90-8

Chemical Formula: C24H16F6N6O

Exact Mass: 518.1290

Molecular Weight: 518.42

Elemental Analysis: C, 55.60; H, 3.11; F, 21.99; N, 16.21; O, 3.09

Price and Availability

Size	Price	Availability
5mg	USD 350.00	2 Weeks
10mg	USD 550.00	2 Weeks
25mg	USD 950.00	2 Weeks

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Related CAS #

927880-90-8

Synonym

CHIR 265; CHIR265; CHIR-265; RAF-265; RAF 265; RAF265.

IUPAC/Chemical Name

1-methyl-5-(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine

InChi Key

YABJJWZLRMPFSI-UHFFFAOYSA-N

InChi Code

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)

SMILES Code

FC(C1=CC=C(NC2=NC3=CC(OC4=CC(C5=NC(C(F)(F)F)=CN5)=NC=C4)=CC=C3N2C)C=C1)(F)F

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in ethanol

Shelf Life

>5 years if stored properly

Drug Formulation

This drug may be formulated in ethanol

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

CHIR-265 is an orally bioavailable small molecule with potential antineoplastic activity.CHIR-265 binds and inhibits Raf kinases, which may result in a reduction of tumor cell growth and proliferation, and tumor cell death. In addition, this agent inhibits vascular endothelial growth factor receptor type 2 (VEGFR-2), thereby disrupting tumor angiogenesis. Raf kinases are critical enzymes in the Ras/Raf/MEK/ERK signaling pathway and are frequently upregulated in neoplasms. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) Current developer: Novartis International AG.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

RAF-265 binds and inhibits Raf kinases, which may result in a reduction of tumor cell growth and proliferation, and tumor cell death. RAF-265 inhibits vascular endothelial growth factor receptor type 2 (VEGFR-2), thereby disrupting tumor angiogenesis. Raf kinases are critical enzymes in the Ras/Raf/MEK/ERK signaling pathway and are frequently upregulated in neoplasms.

In vitro activity:

RAF-265inhibited Erk1/2 phosphorylation but strongly induced Akt phosphorylation and VEGF secretion. These results suggest the existence of a compensatory feedback loop on PI3K-Akt signaling. Combined treatment of RAF-265 with RAD001 or NVP-BEZ235 was more efficient than single treatment with either kinase inhibitor. Reference: Cancer Lett. 2010 Sep 1;295(1):100-9. https://pubmed.ncbi.nlm.nih.gov/20356670/

In vivo activity:

RAF-265 produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels in patients with advanced or metastatic melanoma. Antitumor activity occurred in patients with BRAF-mutant and BRAF-WT disease. Reference: Cancer Med. 2017 Aug;6(8):1904-1914. https://pubmed.ncbi.nlm.nih.gov/28719152/

	Solvent	mg/mL	mM
Solubility
	Ethanol	10.0	19.29

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 518.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Zitzmann K, Rüden Jv, Brand S, Göke B, Lichtl J, Spöttl G, Auernhammer CJ. Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. Cancer Lett. 2010 Sep 1;295(1):100-9. doi: 10.1016/j.canlet.2010.02.018. Epub 2010 Mar 30. PMID: 20356670. 2. Mordant P, Loriot Y, Leteur C, Calderaro J, Bourhis J, Wislez M, Soria JC, Deutsch E. Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination. Mol Cancer Ther. 2010 Feb;9(2):358-68. doi: 10.1158/1535-7163.MCT-09-1014. Epub 2010 Feb 2. PMID: 20124452. 3. Izar B, Sharfman W, Hodi FS, Lawrence D, Flaherty KT, Amaravadi R, Kim KB, Puzanov I, Sosman J, Dummer R, Goldinger SM, Lam L, Kakar S, Tang Z, Krieter O, McDermott DF, Atkins MB. A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status. Cancer Med. 2017 Aug;6(8):1904-1914. doi: 10.1002/cam4.1140. Epub 2017 Jul 18. PMID: 28719152; PMCID: PMC5548886. 4. Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T, Zaja-Milatovic S, Dahlman KB, Amiri KI, Jiang A, Lu P, Shyr Y, Stuart DD, Levy S, Sosman JA, Richmond A. RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012 Apr 15;18(8):2184-98. doi: 10.1158/1078-0432.CCR-11-1122. Epub 2012 Feb 20. Erratum in: Clin Cancer Res. 2012 Aug 15;18(16):4475. PMID: 22351689; PMCID: PMC3724517.

In vitro protocol:

In vivo protocol:

1. Izar B, Sharfman W, Hodi FS, Lawrence D, Flaherty KT, Amaravadi R, Kim KB, Puzanov I, Sosman J, Dummer R, Goldinger SM, Lam L, Kakar S, Tang Z, Krieter O, McDermott DF, Atkins MB. A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status. Cancer Med. 2017 Aug;6(8):1904-1914. doi: 10.1002/cam4.1140. Epub 2017 Jul 18. PMID: 28719152; PMCID: PMC5548886. 2. Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T, Zaja-Milatovic S, Dahlman KB, Amiri KI, Jiang A, Lu P, Shyr Y, Stuart DD, Levy S, Sosman JA, Richmond A. RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012 Apr 15;18(8):2184-98. doi: 10.1158/1078-0432.CCR-11-1122. Epub 2012 Feb 20. Erratum in: Clin Cancer Res. 2012 Aug 15;18(16):4475. PMID: 22351689; PMCID: PMC3724517.

1: Rajadurai A, Tsao H. Identification of Collagen-Suppressive Agents in Keloidal Fibroblasts Using a High-Content, Phenotype-Based Drug Screen. JID Innov. 2023 Nov 22;4(2):100248. doi: 10.1016/j.xjidi.2023.100248. PMID: 38303762; PMCID: PMC10831310. 2: Ercoli MF, Ramos PZ, Jain R, Pilotte J, Dong OX, Thompson T, Wells CI, Elkins JM, Edwards AM, Couñago RM, Drewry DH, Ronald PC. An open source plant kinase chemogenomics set. Plant Direct. 2022 Nov 25;6(11):e460. doi: 10.1002/pld3.460. PMID: 36447653; PMCID: PMC9694430. 3: Wang J, Tian WJ, Li CC, Zhang XZ, Fan K, Li SL, Wang XJ. Small-Molecule RAF265 as an Antiviral Therapy Acts against PEDV Infection. Viruses. 2022 Oct 15;14(10):2261. doi: 10.3390/v14102261. PMID: 36298816; PMCID: PMC9611448. 4: Li CC, Chi XJ, Wang J, Potter AL, Wang XJ, Yang CJ. Small molecule RAF265 as an antiviral therapy acts against HSV-1 by regulating cytoskeleton rearrangement and cellular translation machinery. J Med Virol. 2023 Jan;95(1):e28226. doi: 10.1002/jmv.28226. Epub 2022 Oct 25. PMID: 36251738. 5: Xiao Z, Liu F, Cheng J, Wang Y, Zhou W, Zhang Y. B-Raf inhibitor vemurafenib counteracts sulfur mustard-induced epidermal impairment through MAPK/ERK signaling. Drug Chem Toxicol. 2023 Mar;46(2):226-235. doi: 10.1080/01480545.2021.2021927. Epub 2022 Jan 5. PMID: 34986718. 6: Del Curatolo A, Conciatori F, Cesta Incani U, Bazzichetto C, Falcone I, Corbo V, D'Agosto S, Eramo A, Sette G, Sperduti I, De Luca T, Marabese M, Shirasawa S, De Maria R, Scarpa A, Broggini M, Del Bufalo D, Cognetti F, Milella M, Ciuffreda L. Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models. J Exp Clin Cancer Res. 2018 Jul 9;37(1):140. doi: 10.1186/s13046-018-0820-5. PMID: 29986755; PMCID: PMC6038340. 7: Byrne DP, Li Y, Ngamlert P, Ramakrishnan K, Eyers CE, Wells C, Drewry DH, Zuercher WJ, Berry NG, Fernig DG, Eyers PA. New tools for evaluating protein tyrosine sulfation: tyrosylprotein sulfotransferases (TPSTs) are novel targets for RAF protein kinase inhibitors. Biochem J. 2018 Aug 14;475(15):2435-2455. doi: 10.1042/BCJ20180266. PMID: 29934490; PMCID: PMC6094398. 8: Izar B, Sharfman W, Hodi FS, Lawrence D, Flaherty KT, Amaravadi R, Kim KB, Puzanov I, Sosman J, Dummer R, Goldinger SM, Lam L, Kakar S, Tang Z, Krieter O, McDermott DF, Atkins MB. A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status. Cancer Med. 2017 Aug;6(8):1904-1914. doi: 10.1002/cam4.1140. Epub 2017 Jul 18. PMID: 28719152; PMCID: PMC5548886. 9: Asati V, Bharti SK, Mahapatra DK. Mutant B-Raf Kinase Inhibitors as Anticancer Agents. Anticancer Agents Med Chem. 2016;16(12):1558-1575. doi: 10.2174/1871520616666160606101848. PMID: 27264268. 10: Dunna NR, Kandula V, Girdhar A, Pudutha A, Hussain T, Bandaru S, Nayarisseri A. High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma. Asian Pac J Cancer Prev. 2015;16(16):7089-95. doi: 10.7314/apjcp.2015.16.16.7089. PMID: 26514495. 11: Williams TE, Subramanian S, Verhagen J, McBride CM, Costales A, Sung L, Antonios-McCrea W, McKenna M, Louie AK, Ramurthy S, Levine B, Shafer CM, Machajewski T, Renhowe PA, Appleton BA, Amiri P, Chou J, Stuart D, Aardalen K, Poon D. Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma. ACS Med Chem Lett. 2015 Aug 3;6(9):961-5. doi: 10.1021/ml500526p. PMID: 26396681; PMCID: PMC4569875. 12: Bertazza L, Barollo S, Radu CM, Cavedon E, Simioni P, Faggian D, Plebani M, Pelizzo MR, Rubin B, Boscaro M, Pezzani R, Mian C. Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells. J Cell Mol Med. 2015 Sep;19(9):2244-52. doi: 10.1111/jcmm.12612. Epub 2015 Jun 17. PMID: 26081844; PMCID: PMC4568928. 13: Chow AK, Cheng NS, Lam CS, Ng L, Wong SK, Wan TM, Man JH, Cheung AH, Yau TC, Poon JT, Law WL, Pang RW. Preclinical analysis of the anti-tumor and anti- metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma. Mol Cancer. 2015 Apr 11;14:80. doi: 10.1186/s12943-015-0352-y. PMID: 25884645; PMCID: PMC4481075. 14: Hirschi B, Gallmeier E, Ziesch A, Marschall M, Kolligs FT. Genetic targeting of B-RafV600E affects survival and proliferation and identifies selective agents against BRAF-mutant colorectal cancer cells. Mol Cancer. 2014 May 24;13:122. doi: 10.1186/1476-4598-13-122. PMID: 24885690; PMCID: PMC4035728. 15: Urner-Bloch U, Urner M, Stieger P, Galliker N, Winterton N, Zubel A, Moutouh-de Parseval L, Dummer R, Goldinger SM. Transient MEK inhibitor- associated retinopathy in metastatic melanoma. Ann Oncol. 2014 Jul;25(7):1437-1441. doi: 10.1093/annonc/mdu169. Epub 2014 May 26. PMID: 24864047. 16: Barollo S, Bertazza L, Baldini E, Ulisse S, Cavedon E, Boscaro M, Pezzani R, Mian C. The combination of RAF265, SB590885, ZSTK474 on thyroid cancer cell lines deeply impact on proliferation and MAPK and PI3K/Akt signaling pathways. Invest New Drugs. 2014 Aug;32(4):626-35. doi: 10.1007/s10637-014-0108-3. Epub 2014 May 13. PMID: 24821574. 17: Thumar J, Shahbazian D, Aziz SA, Jilaveanu LB, Kluger HM. MEK targeting in N-RAS mutated metastatic melanoma. Mol Cancer. 2014 Mar 4;13:45. doi: 10.1186/1476-4598-13-45. PMID: 24588908; PMCID: PMC3945937. 18: Grimaldi AM, Cassidy PB, Leachmann S, Ascierto PA. Novel approaches in melanoma prevention and therapy. Cancer Treat Res. 2014;159:443-55. doi: 10.1007/978-3-642-38007-5_25. PMID: 24114495. 19: Huang T, Karsy M, Zhuge J, Zhong M, Liu D. B-Raf and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 25;6:30. doi: 10.1186/1756-8722-6-30. PMID: 23617957; PMCID: PMC3646677. 20: Roller DG, Axelrod M, Capaldo BJ, Jensen K, Mackey A, Weber MJ, Gioeli D. Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma. Mol Cancer Ther. 2012 Nov;11(11):2505-15. doi: 10.1158/1535-7163.MCT-12-0461. Epub 2012 Sep 7. PMID: 22962324; PMCID: PMC3496043.