1. Academic Validation
  2. Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005

Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005

  • J Med Chem. 2021 Aug 26;64(16):11886-11903. doi: 10.1021/acs.jmedchem.1c00388.
Patrick Papa 1 Brandon Whitefield 1 Deborah S Mortensen 1 Dan Cashion 1 Dehua Huang 1 Eduardo Torres 1 Jason Parnes 1 John Sapienza 1 Joshua Hansen 1 Matthew Correa 1 Mercedes Delgado 1 Roy Harris 1 Sayee Hegde 1 Stephen Norris 1 Sogole Bahmanyar 1 Veronique Plantevin-Krenitsky 1 Zheng Liu 1 Katerina Leftheris 1 Ashutosh Kulkarni 1 Brydon Bennett 1 Eun Mi Hur 2 Garth Ringheim 2 Godrej Khambatta 1 Henry Chan 1 Jeffrey Muir 1 Kate Blease 1 Kelven Burnett 1 Laurie LeBrun 1 Lisa Morrison 1 Maria Celeridad 1 Roli Khattri 1 Brian E Cathers 1
Affiliations

Affiliations

  • 1 Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
  • 2 Bristol Myers Squibb, 86 Morris Avenue, Summit, New Jersey 07901, United States.
Abstract

The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.

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