2. Academic Validation
  3. Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1

  • ACS Med Chem Lett. 2021 Feb 19;12(3):443-450. doi: 10.1021/acsmedchemlett.0c00660.
Andrew P Degnan 1,  Godwin K Kumi 1,  Christopher W Allard 2,  Erika V Araujo 2,  Walter L Johnson 3,  Kurt Zimmermann 2,  Bradley C Pearce 2,  Steven Sheriff 1,  Alan Futran 1,  Xin Li 1,  Gregory A Locke 1,  Dan You 4,  John Morrison 1,  Karen E Parrish 1,  Caitlyn Stromko 1,  Anwar Murtaza 1,  Jinqi Liu 1,  Benjamin M Johnson 4,  Gregory D Vite 1,  Mark D Wittman 4
Affiliations

Affiliations

  • 1 Research & Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543, United States.
  • 2 Research & Development, Bristol Myers Squibb Company, Wallingford, Connecticut 06492, United States.
  • 3 Research & Development, Bristol Myers Squibb Company, Redwood City, California 94063, United States.
  • 4 Research & Development, Bristol Myers Squibb Company, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
PMID: 33732413 DOI: 10.1021/acsmedchemlett.0c00660
Abstract

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal Cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138742
    99.33%, HPK1抑制剂
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