Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.,Journal of Medicinal Chemistry

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Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-17 , DOI: 10.1021/acs.jmedchem.9b01888
Nina Reßing _{1,

2} , Melf Sönnichsen ₃ , Jeremy D Osko ₄ , Andrea Schöler ₁ , Julian Schliehe-Diecks ₃ , Alexander Skerhut ₅ , Arndt Borkhardt ₃ , Julia Hauer ₆ , Matthias U Kassack ₅ , David W Christianson ₄ , Sanil Bhatia ₃ , Finn K Hansen _{1,

2}

Affiliation

Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure–activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.

中文翻译：

具有分叉封端基团的选择性组蛋白脱乙酰酶 6 (HDAC6) 抑制剂的多组分合成、结合模式和构效关系。

组蛋白去乙酰化酶 6 (HDAC6) 是治疗癌症、神经退行性疾病、炎症和其他疾病的新兴靶点。在这里，我们展示了一系列基于四唑的 HDAC6 抑制剂的多组分合成和构效关系。我们通过研究重组 HDAC 酶和蛋白质乙酰化的抑制作用，发现了热门化合物 NR-160。与 NR-160 复合的 HDAC6 的共晶结构揭示，NR-160 的分叉封端基团与 L1 和 L2 环袋的空间互补性可能是其 HDAC6 选择性抑制的原因。虽然 NR-160 作为针对白血病细胞系的单一药剂仅显示出低细胞毒性，但它在联合实验中显着增强了蛋白酶体抑制剂硼替佐米的细胞凋亡诱导。此外，组合高通量药物筛选显示，当 NR-160 与表柔比星和柔红霉素联合使用时，细胞毒性显着增强。结合硼替佐米和蒽环类药物的协同作用突出了 NR-160 在联合治疗中的潜力。

更新日期：2020-09-24

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