Researchers from the University of Michigan Health Rogel Cancer Center have created a molecule that inhibits signaling from two crucial factors contributing to cancer therapy resistance. Their work on the development and preliminary assessment of the inhibitor, MTX-531, has been published in Nature Cancer.
Led by Judith Sebolt-Leopold, Ph.D., the team discovered MTX-531, a kinase inhibitor capable of selectively blocking both the epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-OH kinase (PI3K).
“By simultaneously targeting EGFR and PI3K, MTX-531 works to dismantle the escape strategies that tumors employ to resist treatment. In some cancers, such as head and neck squamous cell carcinomas, these kinases are known to facilitate resistance to each other’s inhibition,” explained Sebolt-Leopold, who is a research professor in radiology and pharmacology at Michigan Medicine, as well as co-leader of Rogel’s developmental therapeutics initiative.
The research indicates that MTX-531 resulted in tumor shrinkage in various mouse models of head and neck cancer, with the treatment being well tolerated. Additionally, when combined with drugs that target the RAS pathway, MTX-531 showed strong effectiveness against KRAS-mutated gastrointestinal cancers originating in the colon or pancreas.
Unlike other PI3K inhibitors that can cause severe hyperglycemia, potentially forcing the cessation of treatment, MTX-531 does not have this side effect, suggesting it could be a safer treatment alternative.
The innovative formulation of MTX-531 was accomplished using a computational chemistry approach led by Sebolt-Leopold and Christopher Whitehead, Ph.D., a previous member of Leopold’s laboratory and now chief operating officer of MEKanistic Therapeutics, Inc. Their collaboration spans over 20 years, beginning with their joint efforts on Pfizer’s MEK inhibitor project.
Sebolt-Leopold notes that MTX-531 exemplifies their ongoing dedication to furthering cancer research by creating and developing first-in-class therapeutics. “In pharmaceutical labs, there’s often little opportunity to explore the clinical applications of lead candidates in depth,” Sebolt-Leopold shared. “At Michigan Medicine, I enjoy the distinctive chance to take my research on molecular targeted agents to a more applicable level.”
Preparations for advanced development are in progress to back the clinical assessment of MTX-531, and researchers are optimistic that these efforts will eventually lead to the start of clinical trials involving patients.
Additional contributors include Christopher Whitehead, Elizabeth Ziemke, Christy Frankowski-McGregor, Rachel Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Veerabhadran Baladandayuthapani, Scott Kopetz, and Judith Sebolt-Leopold.
Funding sources: National Institutes of Health grants R01CA220199, R01 CA242764, R21 CA267412, R44CA213715, and R41CA261407.
Disclosure: Whitehead and Sebolt-Leopold are named as inventors on patents related to MTX-531, which are held by the University of Michigan and MEKanistic, and they may earn royalty payments from the university. Patent rights for this compound have been licensed to MEKanistic, Inc., a company in which Whitehead and Sebolt-Leopold have a financial stake.
