Funded by The Michael and Carole Marks Family
Multiple lines of evidence suggest that if achievable, inhibiting K-Ras signaling may have therapeutic advantages in cancer. Approximately 30% of all human cancers contain activating Ras mutations making them one of the most common identifiable molecular cancer drivers. Despite almost 30 years of effort, direct inhibitors of Ras family members have failed to achieve success in the clinical setting. Our immediate aim is to develop and evaluate GTP-competitive inhibitors of K-Ras. Our long term goal is to apply this concept to other cancer-related small GTPases and test it as a new therapeutic strategy.
Targeting the GTP binding site of Ras is difficult because it binds to GTP and GDP with high affinity and the intracellular concentrations of GTP and GDP are also high. We recently reported a concept to overcome these obstacles that involves using compounds that form a covalent bond with K-Ras after they enter the GTP binding site. This concept was motivated both by clinically important, time-tested covalent inhibitors like aspirin and penicillin and by recently developed, rationally designed covalent kinase inhibitors such as Ibrutinib and Afatinib which are now FDA approved. Our prototype compound, SML-8-73-1 (SML), is a GDP analogue containing a reactive warhead extending from the beta-phosphate which adds irreversibly to Cysteine 12, a cysteine found in the active site of an oncogenic mutant form of K-Ras that is common in people exposed to cigarette smoke, K-Ras G12C. We have shown that even in the presence of large excesses of GDP and GTP, quantitative complete irreversible binding of SML is observed.
We hypothesize that for non-G12C K-Ras mutants and other cancer-related GTPases the covalent strategy may be applied by targeting a conserved active site lysine. We already know that targeting this lysine with covalent chemistry is possible but we don’t know if this strategy can be adapted to make inhibitors that are selective for particular GTPases and what the impact of these compounds will be on GTPase-mediated signaling. The goal of our work supported by the V Foundation will be to explore this concept by generating and testing new compounds which target the conserved active site lysine.