Structure-Guided Development of NRAS G12D Inhibitors Based on a 5-Azaindole Core
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.
Authors
- Phuc Phan (ORCID: https://orcid.org/0000-0002-3521-6042)
- Naphtali J. Reyna
- Vinay Nair (ORCID: https://orcid.org/0000-0002-1090-4711)
- Yongying Jiang (ORCID: https://orcid.org/0000-0001-7774-0136)
- R Eugene Johnson
- Anna M. Hickey
- Jason B. Cross (ORCID: https://orcid.org/0000-0002-0919-2833)
- E Nagy (ORCID: https://orcid.org/0000-0002-9940-3218)
- Janelle N. Fawver
- Mary Geck (ORCID: https://orcid.org/0009-0000-2927-9402)
- Lisa Maria Mustachio (ORCID: https://orcid.org/0000-0002-8100-7831)
- Michael Soth (ORCID: https://orcid.org/0000-0002-2649-5537)
- Jennifer Bardenhagen (ORCID: https://orcid.org/0009-0003-2442-8327)
- Qi Wu (ORCID: https://orcid.org/0000-0001-7710-4156)
- Philip Jones
- Troy Johnson
- Pijus K. Mandal
- Tuyen Tran
- Hannah Shepard
- Andrea J. Mendiola
- Joseph Marsalek
- Timothy Heffernan
- Joshua B. Cox
- Fei Yu
- Christian Rodriguez
Institutions
- The University of Texas MD Anderson Cancer Center (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00647
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00