2. Academic Validation
  3. Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy

  • J Med Chem. 2024 Aug 22;67(16):14466-14477. doi: 10.1021/acs.jmedchem.4c01232.
Quinn A Bumpers 1,  Robert W Pipal 1,  Anna M Benz-Weeden 1,  James T Brewster 2nd 1,  Adam Cook 1,  Amy L Crooks 1,  Cole Cruz 1,  Natalie C Dwulet 1,  John J Gaudino 1,  Daniel Golec 1,  Jacqueline A Harrison 1,  Dylan P Hartley 1,  Sherif H Hassanien 1,  Erik J Hicken 1,  Dean Kahn 1,  Ellen R Laird 1,  Christine Lemieux 1,  Nicholas Lewandowski 1,  Joseph McCown 1,  Matthew G McDonald 1,  Oren McNulty 1,  Tung-Chung Mou 1,  Phong Nguyen 1,  Lauren Oko 1,  Lisa Pieti Opie 1,  Jennifer Otten 1,  Spencer C Peck 1,  Viktor C Polites 1,  Samuel D Randall 1,  Rachel Z Rosen 1,  Pavel Savechenkov 1,  Helen Simpson 1,  Anurag Singh 1,  Drew Sparks 1,  Kyle Wickersham 1,  Lance Wollenberg 1,  Christina E Wong 1,  Jim Wong 1,  Wen-I Wu 1,  Mohamed S A Elsayed 1,  Ronald J Hinklin 1,  Tony P Tang 1
Affiliations

Affiliation

  • 1 Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
PMID: 39088797 DOI: 10.1021/acs.jmedchem.4c01232
Abstract

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung Cancer (NSCLC), renal Cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the Animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

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