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  2. 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.
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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