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  • Title: Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents.
    Author: Peng X, Chen J, Li L, Sun Z, Liu J, Ren Y, Huang J, Chen J.
    Journal: J Med Chem; 2021 Jun 24; 64(12):8447-8473. PubMed ID: 34097389.
    Abstract:
    Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound 15c was found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC50 = 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC50 values in the range of 30-144 nM. Compound 15c inhibited B16-F10 cancer cell migration and colony formation. In addition, 15c demonstrated significant in vivo antitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, 15c presented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity. Collectively, this work shows that compound 15c represents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.
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