Structure-Guided Development of NRAS G12D Inhibitors Based on a 5-Azaindole Core

ACS Medicinal Chemistry Letters 2026 Open access

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Authors: Joshua B. Cox, Vinay V. Nair, Pijus Kumar Mandal, Naphtali J. Reyna, Tuyen Tran, Lisa Maria Mustachio, Jennifer Bardenhagen, Janelle N. Fawver, Hannah Shepard, Anna M. Hickey, Qi Wu, Christian Rodriguez
+14 more Fei Yu, Phuc Phan, Andrea J. Mendiola, R Eugene Johnson, Roopa Thapar, TROY R. JOHNSON, Yongying Jiang, Jason B. Cross, Mary Geck, Philip Jones, Joseph Marsalek, Timothy Heffernan, Michael Soth, E Nagy
DOI: 10.1021/acsmedchemlett.5c00647
Cited by: 1
References: 14

Abstract

NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided development of IACS-56676, a selective and potent NRAS G12D inhibitor useful as a tool compound for further studies of NRAS biology. The development process revealed key insights into gaining selectivity between NRAS and KRAS proteins. Notably, stabilization of the p-loop and substitution toward Leu 95 while maintaining key interactions with Asp12, Gly60, and Asp69 improved NRAS G12D potency and resulted in selectivity against wild-type KRAS/non-responder.

Fields of Study & Subjects

Melanoma and MAPK Pathways Protein Kinase Regulation and GTPase Signaling Estrogen and related hormone effects

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
2
Pages
425–432
Publication date
22 January 2026
Language
EN