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

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Mutations in RAS oncogenes, particularly KRAS, are implicated in approximately 30% of human cancers.
• KRAS is a key driver of uncontrolled cellular proliferation in solid tumors like pancreatic, lung, and colorectal cancers.
• Historically considered 'undruggable', RAS proteins are now targets for small-molecule inhibitors.

Purpose of the Study:

• To discuss the chemistry and biology of small-molecule inhibitors targeting KRAS proteins.
• To categorize and review commercial and investigational KRAS inhibitors.
• To provide an in-depth discussion of RAS proteins and their inhibitors.

Main Methods:

• Literature review of published studies on KRAS inhibitors over past decades.
• Classification of RAS superfamily proteins.
• Analysis of molecular mechanisms of small-molecule KRAS inhibitors.

Main Results:

• Identification and categorization of various synthetic, semi-synthetic, and natural small-molecule inhibitors of KRAS.
• Overview of KRAS inhibitors from early research to clinical trials.
• Detailed discussion on the chemistry and available biological data for these inhibitors.

Conclusions:

• Significant progress has been made in developing KRAS inhibitors, moving them from 'undruggable' to 'druggable'.
• This review provides a comprehensive resource on KRAS inhibitors for researchers and clinicians.
• Continued research into KRAS inhibitors holds promise for improved cancer therapies.