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Bioorganic & medicinal chemistry
09 07, 2023;92 117423.

Discovery of quinazoline HPK1 inhibitors with high cellular potency.

Momar Toure, Theresa Johnson, Bin Li, Ralf Schmidt, Hong Ma, Constantin Neagu, Andrea Unzue Lopez, Yanping Wang, Satenig Guler, YuFang Xiao, Renate Henkes, Kevin Ho, Susan Zhang, Chia Lin Chu, Uma Mahesh Gundra, Filippos Porichis, Long Li, Christine Katharina Maurer, Zhizhou Fang, Djordje Musil, Maria DiPoto, Emily Friis, Reinaldo Jones, Christopher Jones, James Cummings, Eugene Chekler, Eva Maria Tanzer, Bayard Huck, Brian Sherer
Author Information
  1. Momar Toure: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States. Electronic address: momar.toure@emdserono.com.
  2. Theresa Johnson: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  3. Bin Li: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  4. Ralf Schmidt: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  5. Hong Ma: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  6. Constantin Neagu: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  7. Andrea Unzue Lopez: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  8. Yanping Wang: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  9. Satenig Guler: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  10. YuFang Xiao: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  11. Renate Henkes: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  12. Kevin Ho: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  13. Susan Zhang: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  14. Chia Lin Chu: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  15. Uma Mahesh Gundra: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  16. Filippos Porichis: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  17. Long Li: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  18. Christine Katharina Maurer: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  19. Zhizhou Fang: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  20. Djordje Musil: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  21. Maria DiPoto: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  22. Emily Friis: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  23. Reinaldo Jones: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  24. Christopher Jones: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  25. James Cummings: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  26. Eugene Chekler: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  27. Eva Maria Tanzer: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  28. Bayard Huck: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
  29. Brian Sherer: Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
PMID: 37531921 DOI: 10.1016/j.bmc.2023.117423

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Keywords

HPK1 Inhibitors Kinase Optimization Quinazoline pSLP76

MeSH Term

Mice
Animals
Chlorocebus aethiops
Interleukin-2
Receptors, Antigen, T-Cell
Protein Serine-Threonine Kinases
COS Cells

Chemicals

hematopoietic progenitor kinase 1
Interleukin-2
Receptors, Antigen, T-Cell
Protein Serine-Threonine Kinases
Journal Article

Word Cloud

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