Mekanistic Therapeutics, LLC
U-M Venture Accelerator, 1600 Huron Parkway Ann Arbor, MI 48109
MTX-211, designed through iterative rounds of synthesis, is a novel small molecule that represents a first in class opportunity to selectively inhibit EGFR and PI3K family members. It exhibits favorable pharmaceutical properties and the requisite profile for lead compound advancement: molecular weight of 478, clogP 4.69, rule of 5 compliant, facile synthesis (3 steps from readily available starting materials), 78% oral bioavailability, metabolic stability >60 minute half-life in human and mouse microsomes, cmax 10-100x higher than cellular EC90, strong selectivity toward EGFR and PI3K family members, and pharmacodynamic modulation of EGFR and PI3K pathway signaling in vivo and single agent efficacy in clinically relevant KRAS and BRAF mutant patient-derived colorectal (CRC) xenograft models. By virtue of its dual inhibitory profile against both EGFR and PI3K, MTX-211 is effective against resistance mechanisms to MEK inhibitor monotherapy. This is evidenced by a 300 to 500% increase in life span seen in KRAS or BRAF mutant CRC PDX-bearing mice co-treated with MTX-211 and a MEK inhibitor compared to single agent control arms. Promising preclinical data provide critical proof of concept to validate a clinical development path for this agent that targets the KRASmt or BRAFmt colorectal cancer patient subpopulations. Chemical development of MTX-211 has been initiated to deliver cGMP quality active pharmaceutical ingredient needed for IND-enabing toxicology studies.