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Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor
Jason D Shields1, David Baker2, Amber Y S Balazs1
1Early Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Abstract:
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.
Insights
Researchers developed a selective inhibitor for Hematopoietic progenitor kinase 1 (HPK1), a key target in cancer immunotherapy. This new compound enhances T cell activity and shows promising antitumor effects in preclinical models.
Area of Science:
- Immunology
- Pharmacology
- Drug Discovery
Background:
- Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T cell receptor signaling.
- Nonselective HPK1 inhibitors risk off-target effects on T cell activation.
- Targeting HPK1 is a strategy for enhancing anti-tumor immunity in immuno-oncology.
Purpose of the Study:
- To discover and optimize selective HPK1 inhibitors.
- To develop a compound that enhances T cell activity without inhibiting other kinases.
- To evaluate the therapeutic potential of a novel selective HPK1 inhibitor.
Main Methods:
- Structure-based drug design was employed to optimize pyrazine carboxamide inhibitors.
- Compound 24 (AZ3246) was synthesized and characterized.
- In vitro assays measured IL-2 secretion and kinase inhibition. In vivo studies assessed pharmacokinetic properties and anti-tumor activity in a syngeneic mouse model.
Main Results:
- A highly selective HPK1 inhibitor, compound 24 (AZ3246), was identified.
- Compound 24 induced IL-2 secretion in T cells with an EC50 of 90 nM.
- The compound demonstrated favorable pharmacokinetics for oral administration and significant anti-tumor activity in the EMT6 model.
Conclusions:
- Selective inhibition of HPK1 is achievable and therapeutically relevant.
- Compound 24 represents a promising candidate for immuno-oncology therapies.
- This selective inhibitor enhances T cell function and exhibits anti-tumor efficacy.
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