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Bso death proof download6/13/2023 ![]() In situ click chemistry was employed for screening and to probe the binding sites of biotin protein ligase inhibitors by Abell. ![]() In vivo, antitumor activity of HLI98 or MPD has not been reported due to their limitations in terms of solubility and potency. MPD37, the most potent among such compounds, was shown to bind the MDM2 RING domain. ![]() Like their parent compounds (HLI98), the active MPD compounds inhibit the ubiquitination of MDM2 and p53 in vitro and in cells. It activated p53-dependent transcription and apoptosis and exhibited selectivity in cancer cells containing wild-type p53 over those containing mutant p53.įurther modifications of HLI98 yielded MPD compounds. When primary human fibroblasts were treated with HLI98 compounds, both p53 and MDM2 levels increased while no ubiquitinated p53 was detected, which is consistent with the ability of the compounds to inhibit ubiquitination. It also showed some selectivity for MDM2 compared with other RING finger E3s in cell lines. HLI98 compounds specifically inhibited the RING finger domain of MDM2, and not the regions that interact with p53. identified MDM2 ubiquitin ligase inhibitors, 7-nitro-5-deazaflavin compounds (HLI98s HDM2 Ligase Inhibitor 98), through a high throughput screen of small-molecule libraries of 10,000 compounds using an in vitro MDM2 autoubiquitination assay. Asha Thuraisamy, in Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy, 2019 HLI98 and the Derivative MPD Compounds
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