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Purdue researchers take successful steps in potential cancer treatment

News Reports
Lafayette Journal & Courier
Students walk across Purdue University's campus, Thursday, Oct. 7, 2021 in West Lafayette.

WEST LAFAYETTE, Ind. — Medicinal chemistry researchers at Purdue University are further developing a potential immunotherapy treatment for cancer; this one focused on the particular mutation of an enzyme.

"While recent progress in cancer immunotherapy has led to revolutionary success in multiple cancer types, most cancer patients do not benefit from immunotherapy," Zhong-Yin Zhang, head of the Department of Medicinal Chemistry and Molecular Pharmacology, and director of the Purdue Institute for Drug Discovery, said in a release. "Thus, there is an urgent need for additional strategies."

Zhang, also the distinguished professor of Medicinal Chemistry, the Robert C. and Charlotte P. Anderson chair in Pharmacology, further explained that cancer immunotherapy relies on T-cells to recognize foreign, aggressive substances in the body, such as tumors.

"There is an intricate signaling network within T-cells that determines their activity," Zhang said. "Previous studies have revealed that an enzyme called PTPN22 regulates the critical signals that activate them. People with a mutation in the gene have a lower incidence of cancer than people without the mutation.

"Moreover, mouse studies indicate that both the mutant PTPN22 and PTPN22 knockout show enhanced tumor immunity, establishing PTPN22 as a translatable target for cancer immunotherapy."

Zhang clarified that no PTPN22 inhibitors are available as approved drugs due to their poor selectivity for PTPN22 among similar enzymes and their lack "in vivo" activity. That is, until now, with Zhang and his team having developed a PTPN22 inhibitor that has shown advanced anti-tumor immune responses in mice studies.

"We have developed a novel fragment-based approach to engage both the active site and unique peripheral binding pockets," Zhang said. "We have developed inhibitors with high potency and selectivity as well as excellent in vivo efficacy."

L-1, the "novel lead compound" in the inhibitor, has shown no in vivo side effects and, in fact, leads to reduced tumor growth and enhanced immune infiltration.

"Importantly, we demonstrated in collaboration with colleagues at Johns Hopkins University that PTPN22 inhibition by L-1 can be further leveraged to augment antitumor effects by immune checkpoint inhibitor anti-PD1," Zhang said. "These findings support that small molecule inhibition of PTPN22 is a viable approach for pharmacologic, systemic abrogation of PTPN22 in vivo."

According to Zhang in the release, the next steps to advance this treatment are to design, synthesize and test this next generation of inhibitors.

"We will improve the potency, selectivity and drug-like properties for clinical translation," Zhang said. "The goal is to develop a unique and innovative treatment strategy that has the potential to synergize with other immunotherapies."