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Erschienen in:
2020 | OriginalPaper | Buchkapitel
Large-Scale Prediction of the ARS Family Inhibitors of the Oncogenic KRASG12C Mutant
verfasst von : Anna M. Kulakova, Anna V. Popinako, Maria G. Khrenova
Erschienen in: Large-Scale Scientific Computing
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Abstract
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 KRASG12C. The most prospective ARS-853 has IC\(_{50}\) = 1.6 \(\upmu \)M that is too large for the medicinal applications. We demonstrate that calculated dissociation constants K\(_\mathrm{d}\) 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.