1628838-42-5

Basic information

• Product Name: RAF709
• Synonyms: RAF709
• CAS NO: 1628838-42-5
• Molecular Formula: C28H29F3N4O4
• Molecular Weight: 542.5494696
• Mol File: 1628838-42-5.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 622.7±55.0 °C(Predicted)
• Appearance: /
• Density: 1.321±0.06 g/cm3(Predicted)
• PKA: 11.87±0.70(Predicted)
• CAS DataBase Reference: RAF709(CAS DataBase Reference)
• NIST Chemistry Reference: RAF709(1628838-42-5)
• EPA Substance Registry System: RAF709(1628838-42-5)

Safety Data

• Hazardous Substances Data: 1628838-42-5(Hazardous Substances Data)

Usage

Description

RAF709 is a potent and selective inhibitor of B-RAF and C-RAF kinases, with IC50s of 0.4 nM and 0.5 nM, respectively. It demonstrates high selectivity for RAF kinases, inhibiting only B-RAF, B-RAFV600E, and C-RAF in a panel of 456 kinases with greater than 99% inhibition. RAF709 also inhibits phosphorylation of MEK and ERK with minimal paradoxical activation, stabilizes BRAF-CRAF dimers, and reduces the proliferation of Calu-6 RAS mutant cells. In a Calu-6 mouse non-small cell lung cancer (NSCLC) xenograft model, RAF709 effectively reduces ERK phosphorylation and tumor volume in a dose-dependent manner without affecting total body weight.

Uses

Used in Pharmaceutical Industry:
RAF709 is used as a potent inhibitor for B-RAF and C-RAF kinases, which are commonly associated with various types of cancers. Its high selectivity and efficacy in inhibiting these kinases make it a promising candidate for the development of targeted cancer therapies.
Used in Cancer Research:
RAF709 is used as a research tool to study the role of B-RAF and C-RAF kinases in cancer cell proliferation and tumor growth. Its ability to inhibit MEK and ERK phosphorylation, stabilize BRAF-CRAF dimers, and reduce the proliferation of RAS mutant cells provides valuable insights into the molecular mechanisms underlying cancer development and progression.
Used in Drug Development:
RAF709 is used in the development of novel therapeutic agents for the treatment of non-small cell lung cancer (NSCLC) and other cancers driven by B-RAF and C-RAF mutations. Its effectiveness in reducing ERK phosphorylation and tumor volume in preclinical models highlights its potential as a lead compound for further optimization and clinical evaluation.
Used in Combination Therapy:
RAF709 is used in combination with other targeted therapies or conventional chemotherapeutic drugs to enhance the treatment of cancers with B-RAF and C-RAF mutations. Its ability to inhibit multiple oncological signaling pathways and reduce tumor volume in a dose-dependent manner suggests that it may be a valuable component of combination therapies to improve patient outcomes and overcome drug resistance.

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Relevant articles and documents

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

BIARYL AMIDE COMPOUNDS AS KINASE INHIBITORS

The present invention provides compounds of Formula (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.