Lab compound L-32 slows tumors in animal models

Inside Purdue University's College of Pharmacy, Zhong-Yin Zhang's team has pushed a new molecule from a small-molecule collection into animal testing. Called L-32, the quinolone-based inhibitor reduced growth of syngeneic MC38 tumors while promoting what the researchers describe as robust antitumor immunity.

The target is PTPN22, a protein tyrosine phosphatase — an enzyme that helps regulate immune signaling. PTPN22 is a negative regulator of the immune system, and genetic deletion of the protein has been linked to robust antitumor immunity. Zhang's strategy is to block it with a selective small molecule, potentially unleashing both innate and adaptive immune responses against tumor cells.

The team found L-32 by attaching functionalized small-molecule fragments to a quinolone core. That fragment-based approach produced a compound with improved potency, selectivity and cellular efficacy compared with earlier derivatives. The researchers also report a more favorable pharmacokinetic profile and oral bioavailability, but the findings remain preclinical and come from the research team's own testing.

So what changes, concretely? L-32 gives drug developers a more developed chemical starting point for targeting PTPN22, an underexplored cancer-immunity target that has lacked high-quality small-molecule inhibitors. L-32 remains a lead molecule for the development of anticancer agents.

Zhang's group now plans to optimize L-32 and benchmark its in vivo efficacy in more difficult-to-treat cancers, including pancreatic and liver cancers, as well as cancers resistant to existing immunotherapies. The work was published in the Journal of Medicinal Chemistry, and Purdue Innovates has applied for a U.S. patent covering the inhibitors.