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Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, smallmolecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.nosine monophosphate dehydrogenase (IMPDH) is a major rate-limiting enzyme involved in guanosine and deoxyguanosine biosynthesis and widely expressed in immunocytes (1). There exist two IMPDH isoforms (IMPDH1 and IMPDH2), which are encoded by distinct genes (2, 3). Many inflammation-relevant diseases have been specially characterized by the high expression of isoform II of IMPDH (IMPDH2) in rapidly proliferating immunocytes, rather than the "housekeeping" type I isoform (IMPDH1) in normal human leukocytes and lymphocytes (4, 5). Therefore, selective targeting of IMPDH2 with small molecules is an attractive topic for development of antiinflammation agents with low side effects.Both IMPDH isoforms contain two major domains: the catalytic domain for substrate interaction and the Bateman domain, which is not required for catalytic activity but exerts an important allosteric regulation effect on IMPDH activity by communicating with the catalytic domain (6, 7). By influencing catalytic domain activity, the Bateman domain can regulate IMPDH function and further blocks the downstream-of-inflammation signaling pathways (8, 9). Currently, IMPDH inhibitors are divided into two major categories. One kind of inhibitor, including 6-chloropurine riboside ribavirin and mizoribine, targets the binding pocket of the natural substrate, inosine monophosphate (IMP). Another kind of inhibitor (e.g., mycophenolic acid and thiazole-4-carboxamide adenine dinucleotide) targets the site of the cofactor, NAD + / NADH, which usually leads to low selectivity or even side effects in clinical trials, such as diarrhea and leukopenia (10, 11). Moreover, a third ligand has been speculated to bind to a possible site far from the IMP and NAD + pockets as an allosteric inhibitor. However, an allosteric site for designing selective IMPDH2 inhibitors has been largely unexplored.Natural small molecules remain promising drug sources (12, 13). In the present study, we report that a natural small-molecule probe, sappanone A (SA, Fig.1A), demonstrated significant inhibitory effects on neuroinflammation by directly targetin...