10ra
Human SARM1 TIR domain bound to compound 6
Structural highlights
FunctionSARM1_HUMAN Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.[1] [2] [3] [4] Publication Abstract from PubMedSterile 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. Structure-Based Discovery of Imidazo[4,5-c]pyridine SARM1 Modulators Showing Paradoxical Activation.,Albanese SK, Hopkins BE, Olland AM, Fairman A, Shaikh N, Feng S, Thakkar M, Verras A, Dementiev A, Walkup WG 4th, Atsriku C, Srinivas HD, Allen W, Ashraf K, Bos PH, Hsiao P, Kroeck K, Liu Z, Nagarajan A, Szlenk CT, Svensson M, Johnson ZL, Kapilashrami K, Rubino S, Kaplan A, Levinson AM J Med Chem. 2026 Apr 8. doi: 10.1021/acs.jmedchem.6c00352. PMID:41948869[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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