8WSM

NLRP3 NACHT domain in complex with compound 32

Summary for 8WSM

• Entry DOI: 10.2210/pdb8wsm/pdb
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: inflammasome, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 65056.23

Authors

Akai, S.,Orita, T.,Adachi, T. (deposition date: 2023-10-17, release date: 2023-11-22, Last modification date: 2024-01-03)

Primary citation

Ohba, Y.,Adachi, K.,Furukawa, T.,Nishimaru, T.,Sakurai, K.,Masuo, R.,Inami, T.,Orita, T.,Akai, S.,Adachi, T.,Usui, K.,Hamada, Y.,Mori, M.,Kurimoto, T.,Wakashima, T.,Akiyama, Y.,Miyazaki, S.,Noji, S.
Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide.
Acs Med.Chem.Lett., 14:1833-1838, 2023

PubMed Abstract: The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and bioisosteric replacement are known to be attractive approaches. As the results of our medicinal chemistry campaign, which involved exploration of core motifs using a ring closing approach, a five-membered oxazole-based scaffold was identified, and subsequent implementation of bioisosteric replacement led to discovery of a novel chemical class of NLRP3 inflammasome inhibitor bearing the acylsulfamide group. Further optimization of aniline and sulfamide moieties to improve potency in human whole blood assay led to the identification of the orally bioactive compound in the LPS challenge model. Furthermore, compound attenuated kidney injury in adriamycin-induced glomerulonephritis in mice. These investigations indicated that the NLRP3 inhibitor could be a potential therapeutic agent for glomerulonephritis.

PubMed: 38116417
DOI: 10.1021/acsmedchemlett.3c00433

Experimental method

X-RAY DIFFRACTION (2.7 Å)