Inhibition of Nonfunctional Ras.
Inhibition of Nonfunctional Ras.
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DOI：
10.1016/j.chembiol.2020.12.012
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发表时间：
2021-02-18
影响因子：
8.6
通讯作者：
Gaponenko V
中科院分区：
文献类型：
--
作者：
Nussinov R;Jang H;Gursoy A;Keskin O;Gaponenko V
Intuitively, functional states should be targeted; not nonfunctional ones. So why could drugging the inactive K-Ras4BG12C work – but, drugging the inactive kinase will likely not? The reason is the distinct oncogenic mechanisms. Kinase driver mutations work by stabilizing the active state and/or destabilizing the inactive state. Either way, oncogenic kinases are mostly in the active state. Ras driver mutations work by quelling its deactivation mechanisms, GTP hydrolysis and nucleotide exchange. Covalent inhibitors that bind to the inactive GDP-bound K-Ras4BG12C conformation can thus work. By contrast, in kinases, allosteric inhibitors work by altering the active site conformation to favor orthosteric drugs. From the translational standpoint this distinction is vital: it expedites effective pharmaceutical development and extends the drug classification based on the mechanism of action. Collectively, here we postulate that drug action relates to blocking the mechanism of activation; not to whether the protein is in the active or inactive state. Nussinov et al. describe that the mechanism of mutational activation of kinases differs from Ras. Drug action should relate to the mechanism of activation, not to whether the protein is in active or inactive state. However, allosterically blocking the functional site will work for the inactive kinase and active Ras.
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DOI：
10.1038/nrm3255
发表时间：
2011-12-22
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
K-RAS前化作为潜在的抗癌靶标。
DOI：
10.1007/s10555-020-09902-w
发表时间：
2020-12
期刊：
Cancer metastasis reviews
影响因子：
--
作者：
Baranyi M;Buday L;Hegedűs B
通讯作者：
Hegedűs B
DOI：
10.1158/1078-0432.ccr-14-3214
发表时间：
2015-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cox AD;Der CJ;Philips MR
通讯作者：
Philips MR
影响因子：
5.6
作者：
Barklis, Eric;Stephen, Andrew G.;Alfadhli, Ayna
通讯作者：
Alfadhli, Ayna