Development of MTX-211 for the Treatment of KRAS Mutant Colorectal Cancer

PROJECT SUMMARY
Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit
multiple oncogenic pathways. Its lead agent MTX-211 was discovered in collaboration with the Leopold
laboratory at University of Michigan. The overall objective of this project is to expediently advance MTX-
211 into development for the treatment of KRAS mutant colorectal cancer (CRC). Every year andgt;130,000
new patients are diagnosed with colorectal cancer. At the time of diagnosis, approximately 20% of these
patients present with metastatic disease. Currently, there are no approved treatments for metastatic
CRC patients with activating mutations in KRAS. MTX-211 is a first-in-class highly selective dual inhibitor
of PI3K and EGFR kinases, designed to attack KRAS oncogenic signaling using two orthogonal
mechanisms. As such, it embodies a combination approach in a single molecule. Phase I aims focused
on optimizing the synthetic process to scale-up production of MTX-211 and conducting a pilot mouse
trial of primary xenograft models established from six different patients diagnosed with KRAS mutant
CRC. All milestones were achieved providing preclinical proof-of-concept for pursuit of a clinical
development path for MTX-211 that specifically targets the KRAS mutant CRC population. In Phase II,
we propose to test a broader panel of KRAS mutant CRC models in an expanded efficacy trial that
incorporates molecular profiling to identify prognostic markers that correlate with therapeutic outcome.
At the same time, we propose to carry out early safety studies to further de-risk MTX-211 and strengthen
the case for moving forward to future IND-enabling toxicology studies.NARRATIVE
Public Health Impact: There is an urgent need to develop more effective therapies to improve the low survival
rate for metastatic colorectal cancer, where the prognosis for patients diagnosed with KRAS mutant disease is
especially poor. This project is focused on evaluation of MTX-211, a novel first-in-class agent, that selectively
targets EGFR and PI3 kinase, key signaling molecules implicated in the progression of KRAS mutant
colorectal cancer.