Design, synthesis, and biological evaluation of novel HPK1 inhibitors possessing 3-cyano-quinoline moiety

Area of Science:

• Immunology
• Medicinal Chemistry
• Oncology

Background:

• Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T cell receptor signaling.
• HPK1 inhibition enhances T cell anti-tumor immunity, making it a key target for cancer immunotherapy.

Purpose of the Study:

• To design, synthesize, and evaluate novel HPK1 inhibitors.
• To identify potent HPK1 inhibitors based on a 3-cyano-quinoline scaffold for potential cancer immunotherapy applications.

Main Methods:

• Synthesis of a novel series of 3-cyano-quinoline derivatives.
• In vitro biological evaluation, including HPK1 inhibition assays, IL-2 secretion, and immunosuppression reversal in Jurkat cells.
• Assessment of metabolic stability in mouse liver microsomes and plasma.

Main Results:

• Compound 3a emerged as the most potent HPK1 inhibitor, with an IC50 of 48 nM.
• Compound 3a effectively inhibited SLP76 phosphorylation and boosted IL-2 cytokine secretion.
• Compound 3a reversed PGE2-induced immunosuppression and demonstrated favorable metabolic stability.

Conclusions:

• The study presents a novel series of HPK1 inhibitors with a 3-cyano-quinoline scaffold.
• Compound 3a is a potent HPK1 inhibitor with promising anti-tumor immune-enhancing properties and good metabolic stability.
• This work provides a novel lead compound for the development of HPK1-targeted cancer immunotherapies.