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Inhibition of Nonfunctional Ras.

ABSTRACT: Intuitively, functional states should be targeted; not nonfunctional ones. So why could drugging the inactive K-Ras4B^G12Cwork-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-Ras4B^G12C 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.

SUBMITTER: Nussinov R

PROVIDER: S-EPMC7897307 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Inhibition of Nonfunctional Ras.

Nussinov Ruth R Jang Hyunbum H Gursoy Attila A Keskin Ozlem O Gaponenko Vadim V

Cell chemical biology 20210112 2

Intuitively, functional states should be targeted; not nonfunctional ones. So why could drugging the inactive K-Ras4B<sup>G12C</sup>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 ex ...[more]

PMID: 33440168

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Project description:ImportanceIt is unclear if nonfunctional adrenal adenomas (NFAAs) are associated with increased mortality.ObjectiveTo analyze mortality and causes of death in patients with NFAA.Design, setting, and participantsA national retrospective register-based case-control study was conducted and included 17 726 patients with a diagnosis of adrenal adenoma in Sweden from 2005 to 2019 who were identified and followed up until death or 2020 as well as 124 366 controls without adrenal adenoma. Individuals with diagnoses indicating adrenal hormonal excess or cancer were excluded. Follow-up started after 3 months of cancer-free survival following the date of the NFAA diagnosis. Sensitivity analyses were performed in subgroups of individuals for whom it was assumed that controls would also have undergone computed tomography: those with acute appendicitis (for whom it was assumed that there was no concern of cancer) and in patients with a combination of gallbladder, biliary tract, and pancreas disorders and 6-month and 12-month cancer-free survival following the date of the NFAA diagnosis. The data were analyzed in 2022.ExposuresDiagnosis of NFAA.Main outcomes and measuresThe primary outcome was all-cause mortality among patients with NFAA after adjustment for comorbidities and socioeconomic factors. Secondary outcomes were mortality due to cardiovascular diseases and cancer.ResultsAmong 17 726 cases, 10 777 (60.8%) were women, and the median (IQR) age was 65 (57-73) years; among 124 366 controls, 69 514 (55.9%) were women, and the median (IQR) age was 66 (58-73) years. Among cases, overall mortality during the follow-up period (median, 6.2 years [IQR, 3.3-9.6 years]) was higher compared with controls (hazard ratio [HR] 1.43; 95 CI, 1.38-1.48; adjusted HR [aHR], 1.21; 95% CI, 1.16-1.26). The relative association of NFAA with overall mortality was similar in women and men (aHR, 1.22 [95% CI, 1.15-1.28] vs 1.19 [95% CI, 1.11-1.26]; P < .001 in both groups). In contrast, NFAA was associated with a larger increase in mortality among individuals younger than 65 years (aHR, 1.44; 95% CI, 1.31-1.58) than in older individuals (aHR, 1.15; 95% CI, 1.10-1.20; P < .001 for interaction). Mortality due to cardiovascular diseases was increased (aHR, 1.21; 95% CI, 1.13-1.29), as was mortality due to cancer (aHR, 1.54; 95% CI, 1.42-1.67). The association between NFAA and mortality remained significant and of similar magnitude in all sensitivity analyses.Conclusions and relevanceThe results of this case-control study suggest that NFAA was associated with an increased overall mortality and mortality of cardiovascular disease and cancer. The increase was more pronounced among younger individuals.

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Inhibition of Nonfunctional Ras.

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Inhibition of Nonfunctional Ras.

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