SARM1

Sterile alpha and TIR motif containing 1 — an NAD hydrolase implicated in axonal degeneration. Case study presented by Karen Akinsanya (Schrödinger) at Session I, published with BMS in J. Med. Chem.

Why It Matters for the Dynamic Proteome

SARM1 is a paradigm case for why dynamic biology matters:

Surprise #1 — Cryptic pocket

A liganded structure looked clean. Once a designed molecule engaged, a tryptophan rotated and opened a previously invisible pocket. The team redesigned into it (“Compound 19” in the paper).

Surprise #2 — Biomarker reversal at low dose

In a sciatic nerve model, the biomarker moved correctly at 100 and 50 mg/kg, then reversed at 25 mg/kg — sub-stoichiometric coverage left catalytic sites uncovered. A clinical liability, exposed only by dynamics.

Status

Every classical green gate had been ticked: fly genetics, mouse KO, MoA, multiple disease models, human genetics, ASO validation, iPSCs, inhibitor PoC. None caught the dynamic liabilities. SARM1 is still considered a good target — the question is how you drug it.