%0 Journal Article
%T The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening.
%A Hartman G
%A Humphries P
%A Hughes R
%A Ho A
%A Montgomery R
%A Deshpande A
%A Mahanta M
%A Tronnes S
%A Cowdin S
%A He X
%A Liu F
%A Zhang L
%A Liu C
%A Dou D
%A Li J
%A Spasic A
%A Coll R
%A Marleaux M
%A Hochheiser IV
%A Geyer M
%A Rubin P
%A Fortney K
%A Wilhelmsen K
%J Bioorg Med Chem Lett
%V 102
%N 0
%D 2024 Apr 1
%M 38417632
%F 2.94
%R 10.1016/j.bmcl.2024.129675
%X 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.