Journal Article

Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs

Wu, Jing, Tian, Jun, Wang, Xia, Xiao, Aotian, Wang, Jie

2025

Overview

The RAS signaling pathway, particularly through mutations in KRAS, NRAS, and HRAS, plays a pivotal role in driving oncogenesis in a wide range of cancers. For years, RAS proteins were deemed \"undruggable\" due to their smooth surface and lack of deep binding pockets. However, recent breakthroughs in targeting specific RAS mutations, particularly KRAS G12C , have revolutionized the field. The discovery of covalent inhibitors that bind to an allosteric pocket near the cysteine residue of KRAS G12C has led to the development of FDA-approved drugs, marking a significant milestone in RAS-targeted therapy. This review provides a comprehensive overview of the evolution of direct RAS inhibitors, focusing on the chemical development of small molecule inhibitors, molecular glues, protein degraders, and other emerging strategies. We highlight the structural evolution of KRAS inhibitors, from covalent fragment-based approaches to non-covalent inhibitors and pan-RAS targeting strategies. Additionally, we discuss the clinical progress of key inhibitors, including their efficacy, resistance mechanisms, and combination treatment options. Finally, this review explores other innovative approaches such as cyclopeptide inhibitors and outlines future directions of RAS-targeting strategies. The success of RAS-targeted therapies underscores the transformative potential of overcoming the \"undruggable\" nature of RAS, offering new hope for patients with RAS-driven cancers.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Allosteric properties / Animals / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell growth / Chemical bonds / Chemical evolution / Covalent inhibitors / Cysteine / Drug approval / Drug development / Evolution / FDA approval / Humans / K-Ras protein / Kinases / KRAS inhibitors / Molecular glues / Molecular Targeted Therapy / Mutation / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - metabolism / Neoplasms - pathology / Oncology / Optimization / Protein degraders / Proteins / Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors / Proto-Oncogene Proteins p21(ras) - genetics / ras Proteins - antagonists & inhibitors / ras Proteins - genetics / ras Proteins - metabolism / RAS signaling pathway / Review / Signal transduction / Signal Transduction - drug effects / Tumorigenesis