AI Article Synopsis
- Hematopoietic progenitor kinase 1 (HPK1) is an important target in immune oncology research because it regulates key signaling pathways in immune cells.
- Genetic deletion of HPK1 in T cells enhances their response to activation, and HPK1 knockout mice show improved anti-tumor effects.
- The study details the development of effective HPK1 inhibitors through structure-based drug design, achieving strong potency and increased IL-2 cytokine secretion, which could enhance anti-tumor immune responses.
Article 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.
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| http://dx.doi.org/10.1016/j.bmc.2023.117423 | DOI Listing |
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