9GU4
Crystal structure of NLRP3 in complex with inhibitor NP3-253
This is a non-PDB format compatible entry.
Summary for 9GU4
| Entry DOI | 10.2210/pdb9gu4/pdb |
| Related | 8RI2 |
| Descriptor | NACHT, LRR and PYD domains-containing protein 3, 2-[6-[[(3R)-1-ethylpiperidin-3-yl]amino]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total) |
| Functional Keywords | inhibitor, atpase, inflamasome, immune system |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 64963.91 |
| Authors | Srinivas, H. (deposition date: 2024-09-18, release date: 2024-12-11, Last modification date: 2024-12-25) |
| Primary citation | Mackay, A.,Velcicky, J.,Gommermann, N.,Mattes, H.,Janser, P.,Wright, M.,Dubois, C.,Brenneisen, S.,Ilic, S.,Vangrevelinghe, E.,Stiefl, N.,Boettcher, A.,Schoenboerner, M.,Vogelsanger, M.,Muller-Bentz, S.,Kamke, M.,Rubert, J.,Kauffmann, M.,Desrayaud, S.,Trunzer, M.,Srinivas, H.,Hinniger, A.,von Burg, N.,Beltz, K.,Dekker, C.,Farady, C.J. Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome. J.Med.Chem., 67:20780-20798, 2024 Cited by PubMed Abstract: Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer's disease and cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target. Herein we describe our discovery, characterization, and structure-based optimization of a pyridazine-based series of NLRP3 inhibitors initiating from an high-throughput screening campaign. The scaffold, exemplified by lead molecule , has excellent potency and physicochemical and pharmacokinetic properties, including good brain penetration. The establishment of pharmacokinetic/pharmacodynamic relationships in the periphery and central nervous system in mechanistic models facilitates the use of as a tool to further interrogate the biology of NLRP3 in peripheral and neuroinflammatory models. PubMed: 39574318DOI: 10.1021/acs.jmedchem.4c02350 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.696 Å) |
Structure validation
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