Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.
Quinn A Bumpers, Robert W Pipal, Anna M Benz-Weeden, James T Brewster, Adam Cook, Amy L Crooks, Cole Cruz, Natalie C Dwulet, John J Gaudino, Daniel Golec, Jacqueline A Harrison, Dylan P Hartley, Sherif H Hassanien, Erik J Hicken, Dean Kahn, Ellen R Laird, Christine Lemieux, Nicholas Lewandowski, Joseph McCown, Matthew G McDonald, Oren McNulty, Tung-Chung Mou, Phong Nguyen, Lauren Oko, Lisa Pieti Opie, Jennifer Otten, Spencer C Peck, Viktor C Polites, Samuel D Randall, Rachel Z Rosen, Pavel Savechenkov, Helen Simpson, Anurag Singh, Drew Sparks, Kyle Wickersham, Lance Wollenberg, Christina E Wong, Jim Wong, Wen-I Wu, Mohamed S A Elsayed, Ronald J Hinklin, Tony P Tang
Author Information
Quinn A Bumpers: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States. ORCID
Robert W Pipal: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Anna M Benz-Weeden: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
James T Brewster: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States. ORCID
Adam Cook: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Amy L Crooks: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Cole Cruz: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Natalie C Dwulet: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
John J Gaudino: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Daniel Golec: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Jacqueline A Harrison: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Dylan P Hartley: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Sherif H Hassanien: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Erik J Hicken: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States. ORCID
Dean Kahn: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States. ORCID
Ellen R Laird: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Christine Lemieux: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Nicholas Lewandowski: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Joseph McCown: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Matthew G McDonald: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Oren McNulty: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Tung-Chung Mou: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Phong Nguyen: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Lauren Oko: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Lisa Pieti Opie: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Jennifer Otten: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Spencer C Peck: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Viktor C Polites: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Samuel D Randall: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Rachel Z Rosen: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Pavel Savechenkov: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Helen Simpson: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Anurag Singh: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Drew Sparks: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Kyle Wickersham: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Lance Wollenberg: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Christina E Wong: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Jim Wong: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Wen-I Wu: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
Mohamed S A Elsayed: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States. ORCID
Ronald J Hinklin: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States. ORCID
Tony P Tang: Pfizer Research & Development 3200 Walnut Street, Boulder, Colorado 80301, United States.
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 with a MET D1228N cell line IC 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.
