Authors:

Levi M Johnson

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Cancer immunotherapy is a cancer treatment method that harnesses the immune system's defensive capabilities against tumors. Recent advancements including immune checkpoint blockade and adoptive cell therapies have found success, however challenges such as limited efficacy, side effects, and poor tissue penetration limit advancement. Addressing these issues is required to develop safer and more effective treatment strategies. SHP1 is a protein tyrosine phosphatase (PTP) expressed in hematopoietic cells that has been found to negatively regulate immune responses. Inhibiting SHP1 in the body causes enhanced anti-tumor activity in T cells and natural killer cells, suggesting SHP1 as a promising therapeutic target. However, PTPs are considered "undruggable" by many due to their highly conserved binding domains. This "undruggable" nature has hindered small molecule inhibitor development until now. Our research led to the molecule M029, which exhibits over 25-fold selectivity for SHP1 versus SHP2 and greater than 60 fold selectivity against other PTPs. M029 demonstrates stability and low toxicity, with oral bioavailability and efficacy shown in vitro and in vivo. In mouse models, M029 delayed tumor progression by enhancing T cell and NK cell activation and infiltration, effects reversed by anti-CD8+ or anti-NK1.1 treatments, confirming its immune-mediated mechanism. Safety assessments revealed no adverse effects at high doses. This study introduces M029 as a potent SHP1 inhibitor with potential for cancer immunotherapy, marking a significant advancement in targeting SHP1 and other challenging protein tyrosine phosphatases. M029's development informs future strategies against these targets, contributing to broader drug discovery efforts in immunotherapy. Keywords: Drug Discovery; Cancer Immunotherapy; Medicinal Chemistry

Source:

Purdue University / 2024

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Co-authors:

Levi M Johnson