Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition of HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in preclinical models, thus it holds promise as a therapeutic strategy in cancer immunotherapy. Herein we report a series of pyrazine carboxamide pyrazoles as selective inhibitors of HPK1. Key to our approach was the development of late-stage functionalisation chemistry which allowed for rapid SAR generation. Through these efforts, we discovered difluoroethyl pyrazole 16a, an <i>in vivo</i> tool which elicited the desired pharmacodynamic response in mice. Further, we describe the optimization of synthetic chemistry which could support preclinical studies of a member of this series of substituted pyrazoles.

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Publication Details

Journal
RSC Medicinal Chemistry
Published
2025-01-01
DOI
https://doi.org/10.1039/d5md00309a
Citations
1
Primary Topic
Synthesis and biological activity
Type
article
Field-Weighted Citation Impact
0.94
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article

Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors

Deanna A. Mele, Randolph Escobar, Alwin G. Schuller, Theresa A. Proia et al.
1 citations
RSC Medicinal Chemistry
Synthesis and biological activity
0.94
article

Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors

Deanna A. Mele, Randolph Escobar, Alwin G. Schuller, Theresa A. Proia, David J. Wagner, Haoran Tang, Tyler Grebe, Jason D. Shields, Marianne Schimpl, A. Pflug, Minwei Ye, Allan Wu, Maryann San Martin, Magdalena Richter, Robert Casella, Neil P. Grimster, Niresh Hariparsad, Kevin Y. Xu, Gayathri Bommakanti, Lucas A. Morrill, Dedong Wu, Ye Wu, James E. Sheppeck, Anthony J. Metrano, Ryan M. Richards, Éric Gosselin, Kathryn A. Giblin, Rachel Howells, Jianyan Wang, Sha Li, Kun Song, Steve Cook, Hadi Rezaei, Gillian M. Lamont
article en
1 citations

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition of HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in preclinical models, thus it holds promise as a therapeutic strategy in cancer immunotherapy. Herein we report a series of pyrazine carboxamide pyrazoles as selective inhibitors of HPK1. Key to our approach was the development of late-stage functionalisation chemistry which allowed for rapid SAR generation. Through these efforts, we discovered difluoroethyl pyrazole 16a, an <i>in vivo</i> tool which elicited the desired pharmacodynamic response in mice. Further, we describe the optimization of synthetic chemistry which could support preclinical studies of a member of this series of substituted pyrazoles.

RSC Medicinal ChemistryVol. 16(8)
AstraZeneca (United Kingdom) (GB), AstraZeneca (United States) (US)
Openalex Percentile: Top 26%
Synthesis and biological activity
0.94
DOIOpen Access PDFOpenAlex
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