2. Academic Validation
  3. Structure-Based Discovery of Imidazo[4,5- c]pyridine SARM1 Modulators Showing Paradoxical Activation

Structure-Based Discovery of Imidazo[4,5- c]pyridine SARM1 Modulators Showing Paradoxical Activation

  • J Med Chem. 2026 Apr 23;69(8):9521-9536. doi: 10.1021/acs.jmedchem.6c00352.
Steven K Albanese 1,  Brittany E Hopkins 1,  Andrea M Olland 2,  Alexis Fairman 3,  Nadim Shaikh 4,  Shulu Feng 1,  Mahesh Thakkar 4,  Andreas Verras 1,  Alexey Dementiev 2,  Ward G Walkup 4th 2,  Christian Atsriku 1,  Harathi D Srinivas 4,  Wayne Allen 2,  Khuram Ashraf 2,  Pieter H Bos 1,  Peng Hsiao 5,  Kyle Kroeck 2,  Zhijian Liu 1,  Anu Nagarajan 1,  Christopher T Szlenk 1,  Mats Svensson 1,  Zachary Lee Johnson 1,  Kanishk Kapilashrami 1,  Stephen Rubino 6,  Andrew Kaplan 3,  Adam M Levinson 1
Affiliations

Affiliations

  • 1 Schrödinger, Inc., New York, New York 10036, United States.
  • 2 Schrödinger, Inc., Framingham, Massachusetts 01702, United States.
  • 3 Bristol Myers Squibb, East Cambridge, Massachusetts 02141, United States.
  • 4 Schrödinger, Inc., Hyderabad, Telangana 500032, India.
  • 5 Schrödinger, Inc., San Diego, California 92122, United States.
  • 6 Schrödinger, Inc., Cambridge, Massachusetts 02142, United States.
PMID: 41948869 DOI: 10.1021/acs.jmedchem.6c00352
Abstract

Sterile Alpha and TIR Motif Containing 1 (SARM1) is an NAD+ hydrolase enzyme implicated in neurological diseases with prominent axonopathies. A reported method for SARM1 inhibition involves the design of small molecules bearing reactive heterocyclic warheads, which intercept the hydrolysis of NAD+ in the active site of SARM1 and subsequently inhibit enzymatic function of the TIR domain. Herein, we describe the discovery of a series of bicyclic SARM1 inhibitors, initially identified via a unique workflow for free-energy perturbation (FEP+) simulations. Subsequent hit expansion efforts identified potent and cell-active inhibitors with slow off-rates, which impart a unique conformational state of W662 in the SARM1 catalytic site, as assessed via X-ray crystallography. Finally, we discuss an identified liability associated with substrate-based SARM1 inhibitors such as 19, whereby insufficient target engagement results in an increase in biomarkers of neurodegeneration at low doses in vivo and exacerbates neuronal degeneration and cell death in vitro.

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