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

Autor: Hartman G; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA. Electronic address: geochem@comcast.net., Humphries P; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Hughes R; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Ho A; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Montgomery R; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Deshpande A; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Mahanta M; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Tronnes S; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Cowdin S; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., He X; HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China., Liu F; HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China., Zhang L; HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China., Liu C; HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China., Dou D; HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China., Li J; HitGen Inc., Shuangliu District, Chengdu, Sichuan 610000, China., Spasic A; WuXi AppTec, 22 Strathmore Road, Natick, MA 01760, USA., Coll R; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK., Marleaux M; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Hochheiser IV; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Geyer M; Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany., Rubin P; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Fortney K; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA., Wilhelmsen K; BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Apr 01; Vol. 102, pp. 129675. Date of Electronic Publication: 2024 Feb 28.
DOI: 10.1016/j.bmcl.2024.129675
Abstrakt: 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 (K D 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: George Hartman, Paul Humphries, Robert Hughes, Andrew Ho, Rusty Montgomery Aditi Deshpande, Maitriyee Mahanta, Sarah Tronnes, Samantha Cowdin, Paul Rubin, Kristen Fortney and Kevin Wilhelmsen are either current or former employees of BioAge Labs. Xu He, Fangchao Liu, Lifang Zhang, Chuan Liu, Dengfeng Dou, and Jin Li are either current or former employees of HitGen, Inc. Aleksander Spasic is a current employee of WuXi AppTec. Rebecca Coll and Matthias Geyer are current Advisors to BioAge Labs.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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