Expanding Addressable KRAS Mutations through the Structure- and Property-Based Design of Dual-State (GDP/GTP), Reversible Pan-KRAS Inhibitors.

Authors

Ryan P Wurz, Jennifer R Allen, John G Allen, Albert Amegadzie, Ning Chen, Josephine Eshon, Kexue Li, Xiaofen Li, Yunxiao Li, Francesco Manoni, Jose M Medina, Primali Navaratne, Liping H Pettus, René Rahimoff, John Stellwagen, Quentin Tercenio, Nicholas Weires, Benjamin Wigman, Michael Yamano, Wei Zhao, Gitte Husemoen, Sebastian Leth-Petersen, David Bauer, Mike J Frohn, Olga A Mukhina, Michelle Boursier, Amit Vaish, Leszek Poppe, Christopher Mohr, Ying-Chu Chen, Gilbert Joseph Diaz, Kevin Gaida, Paul E Hughes, Jawahar Khetan, Deanna Mohn, Tao Osgood, Anne Y Saiki, Karen Rex, Rati Verma, Paul Wang, Huan Rui, Jason Yu, Upendra P Dahal, Yanfei Li, Prashant Agarwal, Teresa Wegesser, Brian A Lanman

Published in

Journal of medicinal chemistry. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Therapeutically targeting mutant KRAS represents a clinically validated approach for the treatment of solid tumors, including lung, colon, and pancreatic cancers. The approval of covalent KRAS^G12C inhibitors, such as sotorasib and adagrasib, has fueled intense interest in expanding KRAS-directed therapies to mutations beyond KRAS^G12C, such as KRAS^G12D, KRAS^G12V, and KRAS^G13D. Here, we describe the structure- and property-based design of reversible inhibitors of diverse oncogenic mutants of KRAS, leading to AM-2383, a pan-KRAS inhibitor that blocks signaling via both the GDP(off)- and GTP(on)-bound states of KRAS, while sparing the closely related RAS isoforms HRAS and NRAS. AM-2383 disrupts signaling downstream of KRAS, potently suppressing the growth of KRAS^G12D and KRAS^G12V tumor xenografts following oral administration. AM-2383 represents an important proof-of-concept that structural insights from prior covalent KRAS^G12C inhibitors can be leveraged in the design of efficacious and well-tolerated inhibitors of diverse KRAS mutations.

PMID:
42446418
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.