| Structural highlights
Function
[CASP1_HUMAN] Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.[1] [2]
Publication Abstract from PubMed
The use of an interleukin beta 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-IL1beta into active IL-1beta, 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.
Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.,Fournier JF, Clary L, Chambon S, Dumais L, Harris CS, 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 AL, Isabet T, Lardy C, Luzy AP, Mathieu C, Mebrouk K, Orfila D, Pascau J, Reverse K, Roche D, Rodeschini V, Hennequin LF J Med Chem. 2018 Apr 24. doi: 10.1021/acs.jmedchem.8b00067. PMID:29648825[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Alnemri ES, Fernandes-Alnemri T, Litwack G. Cloning and expression of four novel isoforms of human interleukin-1 beta converting enzyme with different apoptotic activities. J Biol Chem. 1995 Mar 3;270(9):4312-7. PMID:7876192
- ↑ Feng Q, Li P, Leung PC, Auersperg N. Caspase-1zeta, a new splice variant of the caspase-1 gene. Genomics. 2004 Sep;84(3):587-91. PMID:15498465 doi:http://dx.doi.org/S0888-7543(04)00161-2
- ↑ Fournier JF, Clary L, Chambon S, Dumais L, Harris CS, 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 AL, Isabet T, Lardy C, Luzy AP, Mathieu C, Mebrouk K, Orfila D, Pascau J, Reverse K, Roche D, Rodeschini V, Hennequin LF. Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne. J Med Chem. 2018 Apr 24. doi: 10.1021/acs.jmedchem.8b00067. PMID:29648825 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00067
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