Abstract |
Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cells and is a negative regulator of T cell receptor (TCR) signaling. Recent studies have demonstrated that HPK1 is a promising therapeutic target for cancer immunotherapy. However, despite significant progress in the development of HPK1 inhibitors, none of them has been approved for cancer therapy. Development of HPK1 inhibitors with a structurally distinct scaffold is still needed. Herein, we describe the design and synthesis of a series of HPK1 inhibitors with a 7H-pyrrolo[2,3-d] pyrimidine scaffold, exemplified by 31. Compound 31 showed potent inhibitory activity against HPK1 with an IC50 value of 3.5 nM and favorable selectivity within a panel of kinases. It also potently inhibited the phosphorylation level of SLP76, a substrate of HPK1, and enhanced the IL-2 secretion in Jurkat cells (human T cell leukemia). Our findings provide new clues for further optimization and development to generate HPK1 inhibitors for cancer immunotherapy.
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Authors | Feifei Wu, Huiyu Li, Qi An, Yaoliang Sun, Jinghua Yu, Wenting Cao, Pu Sun, Xingxing Diao, Linghua Meng, Shilin Xu |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 254
Pg. 115355
(Jun 05 2023)
ISSN: 1768-3254 [Electronic] France |
PMID | 37062169
(Publication Type: Journal Article)
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Copyright | Copyright © 2023 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- hematopoietic progenitor kinase 1
- Protein Serine-Threonine Kinases
- Pyrimidines
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Topics |
- Humans
- Protein Serine-Threonine Kinases
- Signal Transduction
- Phosphorylation
- Pyrimidines
(pharmacology)
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