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Discovery of quinazoline HPK1 inhibitors with high cellular potency
Momar Toure1, Theresa Johnson1, Bin Li1
1Discovery & Development Technologies, Medicinal Chemistry, EMD Serono Research & Development Institute, Inc., Billerica, MA 01821, United States.
Abstract:
Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.
Insights
Hematopoietic progenitor kinase 1 (HPK1) inhibition enhances anti-tumor immunity. Researchers discovered potent HPK1 inhibitors using structure-based drug design, showing significant cellular activity and IL-2 secretion.
Area of Science:
- Oncology
- Immunology
- Drug Discovery
Background:
- Hematopoietic progenitor kinase 1 (HPK1) is a validated target in preclinical immune oncology.
- HPK1 regulates critical signaling pathways in adaptive and innate immune cells.
- HPK1 knockout T cells exhibit enhanced TCR activation sensitivity and improved anti-tumor activity in mice.
Purpose of the Study:
- To discover highly potent HPK1 inhibitors.
- To explore HPK1 inhibition for enhanced anti-tumor immune responses.
Main Methods:
- Structure-based drug design.
- High-throughput screening (HTS) hit optimization.
- Cellular assays measuring proximal (pSLP76) and distal (IL-2) biomarkers.
Main Results:
- Discovery of highly potent HPK1 inhibitors starting from a weak HTS hit.
- Inhibitors demonstrated excellent cellular single-digit nanomolar potency.
- Sustained elevation of IL-2 cytokine secretion was observed.
Conclusions:
- HPK1 inhibition is a promising strategy for enhancing anti-tumor immune responses.
- The developed HPK1 inhibitors show potential for further development in oncology.
