1. Academic Validation
  2. Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1

  • J Med Chem. 2023 Mar 20. doi: 10.1021/acs.jmedchem.2c02038.
Rebecca A Gallego 1 Louise Bernier 1 Hui Chen 2 Sujin Cho-Schultz 1 Loanne Chung 1 Michael Collins 1 Matthew Del Bel 1 Jeff Elleraas 1 Cinthia Costa Jones 3 Ciaran N Cronin 1 Martin Edwards 1 Xu Fang 2 Timothy Fisher 3 Mingying He 1 Jacqui Hoffman 1 Ruiduan Huo 2 Mehran Jalaie 1 Eric Johnson 1 Ted W Johnson 1 Robert S Kania 1 Manfred Kraus 3 Jennifer Lafontaine 1 Phuong Le 1 Tongnan Liu 2 Michael Maestre 4 Jean Matthews 1 Michele McTigue 1 Nichol Miller 3 Qiming Mu 2 Xulong Qin 2 Shijian Ren 2 Paul Richardson 1 Allison Rohner 3 Neal Sach 1 Li Shao 2 Graham Smith 1 Ruirui Su 2 Bin Sun 2 Sergei Timofeevski 3 Phuong Tran 1 Shuiwang Wang 2 Wei Wang 1 Ru Zhou 1 Jinjiang Zhu 1 Sajiv K Nair 1
Affiliations

Affiliations

  • 1 Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United States.
  • 2 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 Oncology Research Unit, Pfizer Worldwide Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United States.
  • 4 La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United States.
Abstract

Immune activating agents represent a valuable class of therapeutics for the treatment of Cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of Cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

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