Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors

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.

Automated summary

HPK1 is a potential therapeutic target for cancer immunotherapy as a negative regulator of TCR signaling. In this study, a series of HPK1 inhibitors with a 7H-pyrrolo[2,3-d]pyrimidine scaffold were designed and synthesized, among which compound 31 showed potent inhibitory activity and favorable selectivity. These findings provide new insights for further optimization and development of HPK1 inhibitors for cancer immunotherapy.