Development of Novel Therapeutic Molecules for Treatment of Squamous Head and Neck Cancers

Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively
inhibit multiple oncogenic pathways. Among Mekanistic’s portfolio are dual and highly selective inhibitors of
EGFR and PI3 kinase, which were rationally designed to only target these two critical oncogenes. The
PI3 kinase (PI3K)/AKT/mTOR pathway plays a central role in driving tumor cell survival and progression.
Despite intensive efforts of the pharmaceutical industry, PI3K inhibitors, encompassing isoform selective as
well as pan-PI3K inhibitors, have largely failed to produce single agent activity against solid tumors. EGFR is a
major contributor to the adaptive signaling mechanisms that lead to PI3K inhibitor resistance. Squamous cell
carcinomas, which comprise an area of high unmet medical need, exhibit a high incidence of genomic
alterations in both EGFR and PI3K. A central goal of this project is to provide preclinical proof of concept to
support monotherapy development of a lead EGFR/PI3K inhibitor that is ideally suited to treat squamous head
and neck cancers. Our preliminary data generated in multiple head and neck squamous cancer models
strongly support this line of investigation. Phase I aims are focused on evaluation of the pre-lead molecule
MTX-531 for its antitumor activity against patient-derived head and neck cancer xenografts in parallel with
pharmacokinetic profiling in rats and dogs to assess bioavailability.PROJECT NARRATIVE
Public Health Impact: There is an urgent need to develop more effective therapies to improve the low survival
rate for squamous cell carcinomas of the head and neck. The prognosis for these cancers is especially poor.
This project is focused on evaluation of MTX-531, a novel agent that selectively targets EGFR and PI3 kinase,
that are key signaling molecules implicated in the progression of squamous cell carcinomas of the head and
neck.