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- W3097094670 abstract "Tipifarnib, a drug that targets HRAS through inhibiting farnesyl transferase, is in phase II clinical trials and appears to show activity in tumors harboring oncogenic HRAS mutations (https://kuraoncology.com/pipeline/#tipifarnib). Unfortunately, these drugs are not expected to be effective on KRAS cancers because KRAS, unlike HRAS, can be prenylated by geranylgeranyl transferase following farnesyl transferase inhibition. To address this, we have developed compounds that prevent farnesylation of KRAS 4B by covalent reaction with C185, the site of prenylation. These compounds bind to a pocket in the G-domain that is formed by interaction with the hypervariable region, an interaction that does not seem to occur in other RAS proteins. This existence of this pocket has been demonstrated through biochemical and biophysical analysis, including NMR and small-angle X-ray scattering. The compounds we have developed are active in cells: they prevent proliferation of MEFs driven by oncogenic KRAS proteins but do not affect MEFs supported by myristoylated KRAS G12D C185S at equivalent concentrations. We are currently optimizing these compounds for further preclinical development. Citation Format: Anna Maciag, Yue Yang, David Turner, Marcin Dyba, Vandana Kumari, Brian Smith, Lixin Fan, Stephan Gysin, Andrew Wolfe, Hazem Abdelkarim, Vadim Gaponenko, Felice Lightstone, Dwight Nissley, Frank McCormick. Preventing KRAS processing [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA21." @default.
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- W3097094670 date "2020-05-01" @default.
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- W3097094670 title "Abstract IA21: Preventing KRAS processing" @default.
- W3097094670 doi "https://doi.org/10.1158/1557-3125.ras18-ia21" @default.
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