2. Academic Validation
  3. Structure-Guided Development of NRAS G12D Inhibitors Based on a 5‑Azaindole Core

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

  • ACS Med Chem Lett. 2026 Jan 22;17(2):425-432. doi: 10.1021/acsmedchemlett.5c00647.
Joshua B Cox 1,  Vinay Nair 1,  Pijus Mandal 1,  Naphtali Reyna 1,  Tuyen Tran 1,  Lisa Maria Mustachio 1,  Jennifer Bardenhagen 1,  Janelle Fawver 1,  Hannah Shepard 1,  Anna M Hickey 1,  Qi Wu 1,  Christian Rodriguez 1,  Fei Yu 1,  Phuc Phan 1,  Andrea J Mendiola 1,  Rebecca Johnson 1,  Roopa Thapar 1,  Troy Johnson 1,  Yongying Jiang 1,  Jason B Cross 1,  Mary K Geck Do 1,  Philip Jones 1,  Joseph Marsalek 1,  Timothy Heffernan 1,  Michael J Soth 1,  Edith Nagy 1
Affiliations

Affiliation

  • 1 Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
PMID: 41704364 DOI: 10.1021/acsmedchemlett.5c00647
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.

Keywords

G12D mutant; KRAS inhibitor; NRAS; SBDD; precision medicine; structure-based drug design; targeted therapy.

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