| Structural highlights
Function
WWP1_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF.[1] [2] [3]
Publication Abstract from PubMed
The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC(50) of 158.3 microM (95% CI = 128.7, 195.1 microM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC(50) of 32.7 microM (95% CI = 24.6, 44.3 microM) for WWP1 and 269.2 microM (95% CI = 209.4, 347.9 microM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a pi-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.
Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.,Dudey AP, Rigby JM, Hughes GR, Stephenson GR, Storr TE, Chantry A, Hemmings AM J Enzyme Inhib Med Chem. 2024 Dec;39(1):2394895. doi: , 10.1080/14756366.2024.2394895. Epub 2024 Sep 2. PMID:39223706[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Seo SR, Lallemand F, Ferrand N, Pessah M, L'Hoste S, Camonis J, Atfi A. The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J. 2004 Oct 1;23(19):3780-92. Epub 2004 Sep 9. PMID:15359284 doi:http://dx.doi.org/10.1038/sj.emboj.7600398
- ↑ Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene. 2004 Sep 9;23(41):6914-23. PMID:15221015 doi:http://dx.doi.org/10.1038/sj.onc.1207885
- ↑ Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME, Hunter T, Noel JP. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol Cell. 2003 Jan;11(1):249-59. PMID:12535537
- ↑ Dudey AP, Rigby JM, Hughes GR, Stephenson GR, Storr TE, Chantry A, Hemmings AM. Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases. J Enzyme Inhib Med Chem. 2024 Dec;39(1):2394895. PMID:39223706 doi:10.1080/14756366.2024.2394895
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