MYCOLab Ai Logo - gold and army green

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies

Summary

This research examines how scientists are developing new drugs to target RAS proteins, which are major drivers of various cancers. Once thought impossible to treat, these proteins are now becoming targetable through innovative drug development approaches. The study reviews various compounds that could potentially treat cancers caused by RAS mutations. Impacts on everyday life: – Provides hope for new treatments for previously difficult-to-treat cancers – Could lead to more effective and targeted cancer therapies with fewer side effects – May help extend survival rates for patients with RAS-mutated cancers – Could reduce healthcare costs through more effective treatments – Demonstrates progress in making ‘undruggable’ targets druggable, opening new possibilities for other diseases

Background

RAS mutations are responsible for about 30% of all human cancer types, including pancreatic, lung, and colorectal cancers. While KRAS1 is a pseudogene, mutation of KRAS2 (commonly known as KRAS oncogene) is directly or indirectly associated with human cancers. Among the RAS family, KRAS is the most abundant oncogene related to uncontrolled cellular proliferation in many cancer types including pancreatic carcinoma (over 80%), colon carcinoma (40-50%), lung carcinoma (30-50%), and others.

Objective

To provide a comprehensive review of small-molecule inhibitors (synthetic, semi-synthetic, and natural) of KRAS proteins, including commercial drugs and investigational molecules from preliminary stages to clinical trials. The study aims to present an in-depth discussion of RAS proteins, classify the RAS superfamily, and describe the molecular mechanism of small-molecule RAS inhibitors.

Results

The study identified and classified numerous small-molecule RAS inhibitors into categories including aza heterocyclic, oxoheterocyclic, mixed heterocyclic, carbocyclic, and natural product inhibitors. Several compounds showed promising results in preclinical and clinical studies, with some demonstrating significant potential in treating RAS-mutated cancers. Notable compounds include AMG 510, MRTX849, and various natural products like quercetin and statins.

Conclusion

While RAS proteins were once considered ‘undruggable’, continuous research efforts have shown they are targetable through various small-molecule inhibitors. Despite progress, challenges remain including drug resistance, toxicity, and inconsistent patient outcomes. Further research is needed to develop RAS inhibitors with higher potency and selectivity, lower toxicity, and better resistance profiles.
  • Published in:International Journal of Molecular Sciences,
  • Study Type:Review,
  • Source: 10.3390/ijms23073706
Scroll to Top