Journal Article Review Ahead of print 4 citations
PubMed: 40475242 DOI: 10.1039/d5md00169b
Evolution of structure-guided drug design strategies targeting mutations in codon 12 of KRAS.
RSC Med Chem
Authors: Sadaf Dorandish, Komal Bhayekar, Anuradha Singh, Narva Deshwar Kushwaha, Evan Malin, Sara Serafimovski, Jeremy M Kelm, Navnath S Gavande, Naga Rajiv Lakkaniga
Affiliations
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University Detroit MI 48201 USA +1 (313) 577 2033 +1(313) 577 1523.
- Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines) Dhanbad India 826004 +91 326 223 5550.
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine Detroit MI 48201 USA.
Abstract
KRAS mutations at codon 12 are among the most frequent driver mutations oncogenic alterations in various cancers and associated with aggressive disease and poor clinical outcomes. Historically, KRAS had been a very difficult target due to its strong binding to GDP/GTP and the lack of available druggable binding pockets. Considerable advances have been achieved in generating direct small-molecule inhibitors selectively targeting KRAS G12 mutations. This review discusses the development of approaches to design inhibitors that bind directly to KRAS, starting from the pioneering work of the Shokat group. This review details significant milestones of KRAS-targeted drug discovery and the current impediments in this field. The identification of covalent inhibitors of the KRAS G12C and more recently a direct inhibitor of K-Ras G12C in a GTP-bound state exemplifies the promise of this approach. Structure-guided drug design improved the basis for understanding the mutations in KRAS, notably at codon 12, and the idea has potential for gene therapy. Focusing exclusively on direct and indirect KRAS inhibitors, this review highlights the evolving strategies transforming KRAS from an elusive target to a tractable therapeutic opportunity, offering new hope for patients with KRAS-driven cancers.
MeSH
Genes, Codon, Pharmaceutical Preparations, Drug Design, Neoplasms, Therapeutics, Mutation