Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead

Li, Huiyu; Qi, Wei-liang; Wang, Yu-xiang; Meng, Linghua

doi:10.1016/j.gendis.2021.08.011

Cited by 6 publications

(3 citation statements)

References 84 publications

(165 reference statements)

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“…Hence, KRAS G12C inhibitors essentially trap KRAS G12C in an inactive KRAS-GDP state (off state), hindering a switch to the active KRAS-GTP state (on state), and, thereby, impeding oncogenic activity. This has led to improved drug efficacy and selectivity ( 29 ). Currently, sotorasib and adagrasib are recommended by the National Comprehensive Cancer Network (NCCN) guidelines as a subsequent treatment option for patients with KRAS G12C-mutant NSCLC in second-line or beyond, if no previous KRAS G12C-targeted therapy was given ( 30 ).…”

Section: Clinical Evidence For Kras Inhibition In Kras ...mentioning

confidence: 99%

Resistance to KRAS inhibition in advanced non-small cell lung cancer

Sreter,

Catarata,

von Laffert

et al. 2024

Front. Oncol.

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Lung cancer remains the leading cause of cancer death globally. More than 50% of new cases are diagnosed in an advanced or metastatic stage, thus contributing to the poor survival of such patients. Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in nearly a third of lung adenocarcinoma and have for decades been deemed an ‘undruggable’ target. Yet, in recent years, a growing number of small molecules, such as the GTPase inhibitors, has been investigated in clinical trials of lung cancer patients harboring KRAS mutations, yielding promising results with improved outcomes. Currently, there are only two approved targeted therapies (adagrasib and sotorasib) for advanced or metastatic KRAS-mutated NSCLC from the second-line setting onwards. In this narrative review, we will focus on KRAS, its molecular basis, the role of its co-mutations, clinical evidence for its inhibition, putative mutation to resistance, and future strategies to overcome resistance to KRAS inhibition.

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Section: Clinical Evidence For Kras Inhibition In Kras ...mentioning

confidence: 99%

Resistance to KRAS inhibition in advanced non-small cell lung cancer

Sreter,

Catarata,

von Laffert

et al. 2024

Front. Oncol.

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“…Mutant K-ras is a potential drug target and however, inhibitors directly against this onco-protein have not been successful, due to the complexity of Ras involved in regulating multiple downstream effectors and interconnecting with various parallel signaling pathways. Recently, a set of small molecules that can covalently bind to the switch-I and –II pockets of mutant K-ras G12C provides the hope in treating cancers harboring oncogenic K-ras Several candidates, such as AMG510, ARS3248 and MRTX849, are generated and currently in clinical trials for treating solid tumors like pancreatic, colon and lung cancers [ 86 ]. Among these candidates, AMG510 (sotorasib, LUMAKRAS™) is the first one approved by FDA for treating K-ras G12C lung cancer patients.…”

Section: Current Therapeutics For Pancreatic Cancermentioning

confidence: 99%

A comprehensive review of pancreatic cancer and its therapeutic challenges

Jiang

Fagman

et al. 2022

Aging

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Pancreatic cancer is a devastating and lethal human malignancy with no curable chemo-treatments available thus far. More than 90% of pancreatic tumors are formed from ductal epithelium as pancreatic ductal adenocarcinoma (PDAC), which often accompany with the expression of mutant K-ras. The incidences of pancreatic cancer are expected to increase rapidly worldwide in the near future, due to environmental pollution, obesity epidemics and etc. The dismal prognosis of this malignancy is contributed to its susceptibility to tumor micro-metastasis from inception and the lack of methods to detect precursor lesions at very early stages of the onset until clinical symptoms occur. In recent years, basic and clinical studies have been making promising progresses for discovering markers to determine the subtypes or stages of this malignancy, which allow effectively implementing personalized therapeutic interventions. The purpose of this review is to discuss the existing knowledge of the molecular mechanisms of pancreatic cancer and the current state of treatment options with the emphasis on targeting therapeutic approaches. The specific focuses are on the molecular mechanisms of the disease, identifications of drug resistance, establishment of immune escaping mechanisms as well as potential of targeting identified pathways in combinations with existing chemo-drugs.www.aging-us.com AGINGpancreatic cancer risk and onset. The majority of the incidences of pancreatic cancer occur sporadically and the disease is often accompanied with genetic abnormalities in somatic cells. Studies have indicated that unlike familial cancer syndromes for gastrointestine/colon or breast, pancreatic cancer has very low penetrance with less than 10% of the cases to be linked to a familial setting [3,4]. Among many genetic lesions detected in pancreatic cancer, active mutant K-ras is one that occurs in early stages of pancreatic tumorigenesis, followed by inactivation of several tumor suppressors, including p53, p16 INK4a , and others (such as SMAD4/DPC4, MLH1, LKB1, PRSS1, and BRCA2) [3,4].

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“…These molecules install low reactivity warheads (i.e.,: the electrophile moiety of the ligand) on a molecular scaffold with high binding affinity with the target structure, resulting in less promiscuity. , An example of TCIs is represented by molecules bearing acrylamide warheads. These molecules have been extensively used to design targeted covalent inhibitors for aiming at non-catalytic residues in different protein families, such as kinases and enzymes, of which EGFR and KRAS are notable examples, where selectivity is challenging to achieve with conventional binders. TCIs target the mutant G12C of KRAS, which is located close to an allosteric pocket that has been found difficult to target with noncovalent ligands .…”

Section: Introductionmentioning

confidence: 99%

Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species

Bianco,

Holcomb,

Santos-Martins

et al. 2023

J. Chem. Inf. Model.

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Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead

Cited by 6 publications

References 84 publications

Resistance to KRAS inhibition in advanced non-small cell lung cancer

Resistance to KRAS inhibition in advanced non-small cell lung cancer

A comprehensive review of pancreatic cancer and its therapeutic challenges

Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species

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