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Feng, Yongmei; Sessions, E. Hampton; Zhang, Fan; Ban, Fuqiang; Placencio-Hickok, Veronica; Ma, Chen-Ting; Zeng, Fu-Yue; Pass, Ian; Terry, David B.; Cadwell, Gregory; Bankston, Laurie A.; Liddington, Robert C.; Chung, Thomas D.Y.; Pinkerton, Anthony B.; Sergienko, Eduard; Gleave, Martin; Bhowmick, Neil A.; Jackson, Michael R.; Cherkasov, Artem; Ronai, Ze'ev A.
Cancer letters, 05/2019, Letnik: 449Journal Article
Inhibition of ubiquitin ligases with small molecule remains a very challenging task, given the lack of catalytic activity of the target and the requirement of disruption of its interactions with other proteins. Siah1/2, which are E3 ubiquitin ligases, are implicated in melanoma and prostate cancer and represent high-value drug targets. We utilized three independent screening approaches in our efforts to identify small-molecule Siah1/2 inhibitors: Affinity Selection-Mass Spectrometry, a protein thermal shift-based assay and an in silico based screen. Inhibitors were assessed for their effect on viability of melanoma and prostate cancer cultures, colony formation, prolyl-hydroxylase-HIF1α signaling, expression of selected Siah2-related transcripts, and Siah2 ubiquitin ligase activity. Several analogs were further characterized, demonstrating improved efficacy. Combination of the top hits identified in the different assays demonstrated an additive effect, pointing to complementing mechanisms that underlie each of these Siah1/2 inhibitors. •Three screening campaigns identify small molecule inhibitors to Siah1/2 ubiquitin ligases.•Each screening campaign identifies distinct small molecule Siah1/2 inhibitors.•Growth of melanoma and prostate cancer is inhibited by Siah1/2 inhibitors.•Adapalene and related analogs identified as potent Siah1/2 inhibitors.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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