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  3. The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening

The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening

  • Bioorg Med Chem Lett. 2024 Feb 28:102:129675. doi: 10.1016/j.bmcl.2024.129675.
George Hartman 1,  Paul Humphries 2,  Robert Hughes 2,  Andrew Ho 2,  Rusty Montgomery 2,  Aditi Deshpande 2,  Maitriyee Mahanta 2,  Sarah Tronnes 2,  Samantha Cowdin 2,  Xu He 3,  Fangchao Liu 3,  Lifang Zhang 3,  Chuan Liu 3,  Dengfeng Dou 3,  Jin Li 3,  Aleksander Spasic 4,  Rebecca Coll 5,  Michael Marleaux 6,  Inga V Hochheiser 6,  Matthias Geyer 6,  Paul Rubin 2,  Kristen Fortney 2,  Kevin Wilhelmsen 2
Affiliations

Affiliations

  • 1 BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA. Electronic address: geochem@comcast.net.
  • 2 BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA.
  • 3 HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China.
  • 4 WuXi AppTec, 22 Strathmore Road, Natick, MA 01760, USA.
  • 5 Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK.
  • 6 Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
PMID: 38417632 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.

Keywords

Anti-inflammation; BAL-0028; CADD; DNA-encoded library; IL-18; IL-1β; NLRP3 inflammasome; NLRP3 inhibitor; Pyroptosis; STAND ATPase.

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