Large-Scale Prediction of the ARS Family Inhibitors of the Oncogenic KRAS~(G12C) Mutant

摘要

The KRAS protein is a molecular switch that activates cellular processes, like cell growth and differentiation. The G12C point mutation of the KRAS is found in various cancer cells. It results in the accretion of the GTP-bound active form thus accelerating downstream signalling pathways. Recently ARS family of compounds was suggested as selective covalent inhibitors of the KRAS~(G12C). The most prospective ARS-853 has IC_(50) = 1.6μM that is too large for the medicinal applications. We demonstrate that calculated dissociation constants K_d are proportional to the experimental IC_(50) values and can be utilized as a measure of the inhibitor potency. Using molecular modeling tools we suggest a set of novel compounds with the predicted IC_(50) values more than an order of magnitude lower than that of the ARS-853.