2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Mar 12;63(5):2013-2027. doi: 10.1021/acs.jmedchem.9b00161.
Savithri Ramurthy 1,  Benjamin R Taft 1,  Robert J Aversa 2,  Paul A Barsanti 1,  Matthew T Burger 2,  Yan Lou 1,  Gisele A Nishiguchi 2,  Alice Rico 1,  Lina Setti 1,  Aaron Smith 1,  Sharadha Subramanian 1,  Victoriano Tamez 2,  Huw Tanner 1,  Lifeng Wan 1,  Cheng Hu 1,  Brent A Appleton 1,  Mulugeta Mamo 1,  Laura Tandeske 3,  John E Tellew 4,  Shenlin Huang 4,  Qin Yue 1,  Apurva Chaudhary 5,  Hung Tian 6,  Raman Iyer 6,  A Quamrul Hassan 7,  Lesley A Mathews Griner 7,  Laura R La Bonte 7,  Vesselina G Cooke 7,  Anne Van Abbema 3,  Hanne Merritt 3,  Kalyani Gampa 7,  Fei Feng 7,  Jing Yuan 7,  Yuji Mishina 7,  Yingyun Wang 3,  Jacob R Haling 4,  Sepideh Vaziri 4,  Mohammad Hekmat-Nejad 3,  Valery Polyakov 1,  Richard Zang 1,  Vijay Sethuraman 3,  Payman Amiri 3,  Mallika Singh 3,  William R Sellers 7,  Emma Lees 7,  Wenlin Shao 7,  Michael P Dillon 2,  Darrin D Stuart 7
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
  • 2 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 3 Oncology, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
  • 4 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • 5 Process Research and Development, Chemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, New Jersey 07936, United States.
  • 6 Technical Research & Development, Global Drug Development, Novartis Pharmaceuticals Corp., One Health Plaza, East Hanover, New Jersey 07936, United States.
  • 7 Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
PMID: 31059256 DOI: 10.1021/acs.jmedchem.9b00161
Abstract

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.

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