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Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors
Qinda Ye1, Kai Liu1, Hai-Fen Ye1
1Incyte Research Institute, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
Abstract:
In spite of the great success of immune checkpoint inhibitors in immune-oncology therapy, an urgent need still exists to identify alternative approaches to broaden the scope of therapeutic coverage. Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, functions as a negative regulator of activation signals generated by the T cell antigen receptor. Herein we report the discovery of novel pyrazolopyridine derivatives as selective inhibitors of HPK1. The structure-activity relationship campaign led to the discovery of compound 16, which has shown promising enzymatic and cellular potency with encouraging kinome selectivity. The outstanding pharmacokinetic profiles of 16 in rats and monkeys supported further evaluations of its efficacy and safety in preclinical models.
Insights
Researchers developed novel pyrazolopyridine derivatives as selective inhibitors of Hematopoietic progenitor kinase 1 (HPK1) to improve cancer immunotherapy. Compound 16 demonstrates potent activity and favorable pharmacokinetics for further preclinical development.
Area of Science:
- Immunology
- Medicinal Chemistry
- Pharmacology
Background:
- Immune checkpoint inhibitors have advanced cancer therapy, but broader treatment options are needed.
- Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T cell receptor signaling, making it a potential therapeutic target.
- Developing selective HPK1 inhibitors could offer new avenues for cancer immunotherapy.
Purpose of the Study:
- To discover and characterize novel pyrazolopyridine derivatives as selective inhibitors of HPK1.
- To identify a lead compound with potent enzymatic and cellular activity and favorable selectivity.
- To evaluate the pharmacokinetic properties of the lead compound in preclinical species.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted to optimize pyrazolopyridine derivatives.
- Enzymatic and cellular assays were used to assess inhibitor potency and selectivity.
- Kinome profiling was performed to evaluate off-target effects.
- Pharmacokinetic studies in rats and monkeys were carried out to assess drug metabolism and distribution.
Main Results:
- A novel series of pyrazolopyridine derivatives targeting HPK1 was identified.
- Compound 16 emerged as a potent and selective HPK1 inhibitor with strong enzymatic and cellular activity.
- Compound 16 exhibited encouraging kinome selectivity, minimizing off-target effects.
- Compound 16 demonstrated favorable pharmacokinetic profiles in rat and monkey models.
Conclusions:
- Novel pyrazolopyridine derivatives are effective inhibitors of HPK1.
- Compound 16 represents a promising drug candidate for further development in cancer immunotherapy.
- The favorable pharmacokinetic properties of compound 16 support its advancement into preclinical efficacy and safety studies.
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