WEST LAFAYETTE, Ind. — Researchers in Purdue University’s College of Pharmacy have developed and validated a novel series of small-molecule inhibitors that promote antitumor immunity and hold promise as novel anticancer agents.

Zhong-Yin Zhang leads a team that has developed L-32, a quinolone-based inhibitor shown to reduce tumor growth in vivo and improve upon the potency, selectivity and cellular efficacy of previous derivatives of the inhibitor.

L-32 targets a protein tyrosine phosphatase (PTP) called PTPN22, a negative regulator of the immune system. Zhang said mutations in PTPN22 are common risk factors for multiple autoimmune disorders, and genetic deletion of PTPN22 leads to robust antitumor immunity.

“Consequently, targeting PTPN22 with small-molecule inhibitors represents an attractive immunotherapeutic strategy to unleash both innate and adaptive immunity against tumor cells,” he said.Zhang said PTPN22 remains underexplored as a therapeutic target despite its known roles in cancer immunity.

“This is due to the scarcity of high-quality small-molecule inhibitors,” he said. “Consequently, we have advanced a novel paradigm to acquire potent and selective PTP inhibitors by targeting both the active site and its nearby unique pockets.”

Zhang is a Distinguished Professor of medicinal chemistry in the Borch Department of Medicinal Chemistry and Molecular Pharmacology, a member of the Purdue Institute for Cancer Research, and director of the Purdue Institute for Drug Discovery.

The research has been published in the Journal of Medicinal Chemistry. Zhang disclosed the quinolone-based PTPN22 inhibitors, including L-32, to the Purdue Innovates Office of Technology Commercialization, which applied for a patent from the U.S. Patent and Trademark Office to protect the intellectual property.

Industry partners interested in developing or commercializing the inhibitors should contact Joe Kasper, assistant director of business development and licensing — life sciences, at jrkasper@prf.org about track code 68996.

 Developing, validating L-32

Zhang and his team discovered quinolone-3-carboxylic acid as a PTPN22 inhibitor from an in-house, druglike small molecule collection.

“Using a fragment-based focused library approach by tethering properly functionalized small molecule fragments to the quinolone core, we identified compound L-32, which displays improved potency, selectivity and cellular efficacy compared to previous compounds,” he said.

Zhang said L-32 has several advantages over the other compounds, including a more favorable pharmacokinetic profile and drug properties including oral bioavailability.

“Importantly, L-32 is superior to early molecules in reducing syngeneic MC38 tumor growth in animal models by promoting robust antitumor immunity, thus offering a promising lead molecule for the development of novel anticancer agents targeting PTPN22,” he said.