{Reference Type}: Journal Article
{Title}: The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening.
{Author}: Hartman G;Humphries P;Hughes R;Ho A;Montgomery R;Deshpande A;Mahanta M;Tronnes S;Cowdin S;He X;Liu F;Zhang L;Liu C;Dou D;Li J;Spasic A;Coll R;Marleaux M;Hochheiser IV;Geyer M;Rubin P;Fortney K;Wilhelmsen K;
{Journal}: Bioorg Med Chem Lett
{Volume}: 102
{Issue}: 0
{Year}: 2024 Apr 1
{Factor}: 2.94
{DOI}: 10.1016/j.bmcl.2024.129675
{Abstract}: NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1β and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen. SPR studies showed that compound 3 binds tightly (KD range 104-123 nM) to the NACHT domain of NLRP3. A CADD analysis of the interaction of compound 3 with the NLRP3 NACHT domain proposes a binding site that is distinct from those of ADP and MCC950 and includes specific site interactions. We anticipate that compound 3 (BAL-0028) and other members of this novel indazole class of neutral inhibitors will demonstrate significantly different physical, biochemical, and biological properties compared to NLRP3 inhibitors previously identified.