6F6R

Crystal structure of human Caspase-1 with N-{3-[1-((S)-2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-(quinoxalin-2-ylamino)-benzamide

Summary for 6F6R

• Entry DOI: 10.2210/pdb6f6r/pdb
• Descriptor: Caspase-1, (3~{S})-3-[[(2~{R})-2-[3-methyl-2,6-bis(oxidanylidene)-5-[[4-(quinoxalin-2-ylamino)phenyl]carbonylamino]pyrimidin-1-yl]propanoyl]amino]-4-oxidanyl-butanoic acid, SULFATE ION, ... (5 entities in total)
• Functional Keywords: caspase-1, nanomolar inhibitor, inflammatory diseases, sp3 hybridization, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: P29466 P29466
• Total number of polymer chains: 2
• Total formula weight: 31029.42

Authors

Fournier, J.F.,Clary, L.,Chambon, S.,Dumais, L.,Harris, C.S.,Millois-Barbuis, C.,Pierre, R.,Talano, S.,Thoreau, E.,Aubert, J.,Aurelly, M.,Bouix-Peter, C.,Brethon, A.,Chantalat, L.,Christin, O.,Comino, C.,El-Bazbouz, G.,Ghilini, A.L.,Isabet, T.,Lardy, C.,Luzy, A.P.,Mathieu, C.,Mebrouk, K.,Orfila, D.,Pascau, J.,Reverse, K.,Roche, D.,Rodeschini, V.,Hennequin, L.F. (deposition date: 2017-12-06, release date: 2018-05-02, Last modification date: 2024-11-06)

Primary citation

Fournier, J.F.,Clary, L.,Chambon, S.,Dumais, L.,Harris, C.S.,Millois, C.,Pierre, R.,Talano, S.,Thoreau, E.,Aubert, J.,Aurelly, M.,Bouix-Peter, C.,Brethon, A.,Chantalat, L.,Christin, O.,Comino, C.,El-Bazbouz, G.,Ghilini, A.L.,Isabet, T.,Lardy, C.,Luzy, A.P.,Mathieu, C.,Mebrouk, K.,Orfila, D.,Pascau, J.,Reverse, K.,Roche, D.,Rodeschini, V.,Hennequin, L.F.
Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.
J. Med. Chem., 61:4030-4051, 2018

PubMed Abstract: The use of an interleukin β antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1β into active IL-1β, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

PubMed: 29648825
DOI: 10.1021/acs.jmedchem.8b00067

Experimental method

X-RAY DIFFRACTION (1.8 Å)