5n1b
hPAD4 crystal complex with AFM-14ahPAD4 crystal complex with AFM-14a
Structural highlights
DiseasePADI4_HUMAN Genetic variations in PADI4 are a cause of susceptibility to rheumatoid arthritis (RA) [MIM:180300. It is a systemic inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Note=Could have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues, leading, in a cytokine-rich milieu, to a break in tolerance to citrullinated peptides processed and presented in the appropriate HLA context.[1] FunctionPADI4_HUMAN Catalyzes the citrullination/deimination of arginine residues of proteins. Citrullinates histone H3 at 'Arg-8' and/or 'Arg-17' and histone H4 at 'Arg-3', which prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.[2] [3] Publication Abstract from PubMedProtein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated. Development of a Selective Inhibitor of Protein Arginine Deiminase 2.,Muth A, Subramanian V, Beaumont E, Nagar M, Kerry P, McEwan P, Srinath H, Clancy K, Parelkar S, Thompson PR J Med Chem. 2017 Apr 13;60(7):3198-3211. doi: 10.1021/acs.jmedchem.7b00274. Epub , 2017 Mar 31. PMID:28328217[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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