Discovery of diaminopyrimidine carboxamide HPK1 inhibitors as preclinical immunotherapy tool compounds

DOI: 10.1021/acsmedchemlett.1c00096

Authors: Brandon A. Vara (Merck & Co., Inc) , Samuel M. Levi (Merck & Co., Inc) , Abdelghani Achab (Merck & Co., Inc) , David A. Candito (Merck & Co., Inc) , Xavier Fradera (Merck & Co., Inc) , Charles A. Lesburg (Merck & Co., Inc) , Shuhei Kawamura (Merck & Co., Inc) , Brian M. Lacey (Merck & Co., Inc) , Jongwon Lim (Merck & Co., Inc) , Joey L. Methot (Merck & Co., Inc) , Zangwei Xu (Merck & Co., Inc) , Haiyan Xu (Merck & Co., Inc) , Dustin M. Smith (Merck & Co., Inc) , Jennifer A. Piesvaux (Merck & Co., Inc) , J. Richard Miller (Merck & Co., Inc) , Mark Bittinger (Merck & Co., Inc) , Sheila H. Ranganath (Merck & Co., Inc) , David J. Bennett (Merck & Co., Inc) , Erin F. Dimauro (Merck & Co., Inc) , Alexander Pasternak (Merck & Co., Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 2

State: Published (Approved)
Published: March 2021

Abstract: Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure–activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.

Journal Keywords: HPK1; oncology; immunotherapy; immune-oncology; kinase inhibitor

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 07/04/2021 08:49

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)