منابع مشابه
Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.
Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket...
متن کاملA quantitative systems pharmacology analysis of KRAS G12C covalent inhibitors
The KRAS oncogene is the most common, activating, oncogenic mutation in human cancer. KRAS has proven difficult to target effectively. Two different strategies have recently been described for covalently targeting the most common activating KRAS mutant in lung cancer, KRAS G12C. Previously, we have developed a computational model of the processes that regulate Ras activation and this model has ...
متن کاملQuantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors.
KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, ...
متن کاملBase excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells
KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatments but this feature lacks a mechanistic basis so far. In tumors, KRAS was found to be mutated mostly at codons 12 and 13 and a pool of mutations differing in the base alteration and the amino acid substitution have been described. The different KRAS mutations may differently impact on cance...
متن کاملDifferent metabolic responses to PI3K inhibition in NSCLC cells harboring wild-type and G12C mutant KRAS
KRAS mutations in non-small-cell lung cancer (NSCLC) patients are considered a negative predictive factor and indicate poor response to anticancer treatments. KRAS mutations lead to activation of the PI3K/akt/mTOR pathway, whose inhibition remains a challenging clinical target. Since the PI3K/akt/mTOR pathway and KRAS oncogene mutations all have roles in cancer cell metabolism, we investigated ...
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ژورنال
عنوان ژورنال: Nature Reviews Clinical Oncology
سال: 2019
ISSN: 1759-4774,1759-4782
DOI: 10.1038/s41571-019-0304-3