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Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase. It is emerging as a promising target for the development of drugs to treat cancer and metabolism-related diseases. In this study, we screened 5000 compounds and identified a hit compound 14 bearing a pyrazolone functional group as a novel SIRT5-selective inhibitor. Structure-based optimization of 14 resulted in compound 47 with an IC 50 value of 0.21 ± 0.02 μM and a 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 over SIRT1-3 and SIRT6. Biochemical studies suggest that 47 does not occupy the NAD + -binding pocket and acts as a substrate-competitive inhibitor. The identified potent and selective SIRT5 inhibitors allow further studies as research tools and therapeutic agents. [Display omitted] • Hit compound 14 bearing a pyrazolone skeleton was identified as a SIRT5 inhibitor. • Extensive SAR studies guided by molecular docking were conducted. • Compound 47 showed a 100-fold increased potency as compared to the original hit. [ABSTRACT FROM AUTHOR]

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e 6 -based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e 6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e 6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O 2 and excellent antitumor efficacy in vitro and in vivo. [Display omitted] • The conjugates of chlorin e 6 with Dasatinib or Imatinib were synthesized. • In vitro PDT antitumor activities of all target compounds were investigated. • In vivo antitumor potency and mechanism of preferred compound 10b were evaluated. • In vitro PDT antitumor efficacy of 10b was better than chlorin e 6 and talaporfin. • In vivo PDT antitumor efficacy of 10b was superior to chlorin e 6. [ABSTRACT FROM AUTHOR]

Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1–8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs. HDAC-PROTACs surpass traditional HDAC inhibitors in many aspects, such as higher selectivity, more potent antiproliferative activity, and the ability to disrupt the enzyme-independent functions of a multifunctional protein and overcome drug resistance. Rationally designing HDAC-PROTACs is a main challenge in development because slight variations in chemical structure can lead to drastic effects on the efficiency and selectivity of the degradation. In the future, HDAC-PROTACs can potentially be involved in clinical research with the support of the increased amount of in vivo data, pharmacokinetic evaluation, and pharmacological studies. [Display omitted] • Ten of the eighteen HDACs have been successfully degraded by PROTAC. • HDAC-PROTAC surpass traditional HDAC inhibitors in many aspects. • Rationally designing HDAC-PROTAC is a main challenge in development. [ABSTRACT FROM AUTHOR]