Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma

Zhou, Ruolan; Fang, Shaoyu; Zhang, Qingsen; Hu, Jian; Wang, Mingping; Wang, Chongqing; Zhu, Jü; Shen, Aijun; Chen, Xin; Zheng, Canhui

doi:10.1016/j.bmcl.2018.12.052

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…119 Zheng et al had developed a class of dualtargeted Bcl-2 and HDAC inhibitors suitable for treating multiple myeloma (MM) based on ABT-199. 120 Representative compounds 30a, 30b, and 30c, with the linker lengths of 5, 6, and 7 methylenes, respectively, showed highly selective HDAC6 potency (IC 50 = 28, 28, and 19 nM, respectively). Also, they exhibited strong binding affinities toward Bcl-2 (Figure 10).…”

Section: Hdac6 Inhibitors Bearing Hydroxamic Acid-based Zbgmentioning

confidence: 99%

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

Zhang

Qin-Ma

et al. 2021

J. Med. Chem.

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Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC6 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC6 inhibitors have been effectively used to treat cancers, neurodegenerative diseases, and autoimmune disorders without exerting significant toxic effects. Progress has been made in defining the crystal structures of HDAC6 catalytic domains which has influenced the structure-based drug design of HDAC6 inhibitors. This review summarizes recent literature on HDAC6 inhibitors with particular reference to structural specificity and functional diversity. It may provide up-to-date guidance for the development of HDAC6 inhibitors and perspectives for optimization of therapeutic applications.

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Section: Hdac6 Inhibitors Bearing Hydroxamic Acid-based Zbgmentioning

confidence: 99%

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

Zhang

Qin-Ma

et al. 2021

J. Med. Chem.

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“…A series of Bcl-2/HDAC dual-target inhibitors were designed by changing the tetrahydropyranyl methyl group of venetoclax, a known Bcl-2 inhibitor, into a hydroxamic acid group with different linkers (Figure ). Among them, compounds 28a – g ( n = 5–7) showed potent binding affinity to the Bcl-2 protein and good inhibitory activities against HDAC6 simultaneously. The inhibitory activities of these compounds are comparable to those of their parent compounds, venetoclax and SAHA, respectively.…”

Section: Combination Of Hdac With Bcl-2 Inhibitorsmentioning

confidence: 99%

Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy

et al. 2020

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Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure−activity relationships of these dual-target agents.

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“…Three anti-apoptotic members, BCL-2, BCL-X L and MCL-1, are validated anticancer targets. Zhou et al designed several of BCL-2-HDAC dualtarget inhibitors derived from venetoclax (ABT-199) [135]. Compound 61 showed binding affinity toward HDAC6 and BCL-2 with IC 50 values of 19 and 250 nM, respectively.…”

Section: Nonhydroxamate Acid-derived Inhibitorsmentioning

confidence: 99%

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

Xiao

Zhang

2020

Future Drug. Discov.

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Histone deacetylase 6 (HDAC6) is a unique isozyme in the HDAC family with various distinguished characters. HDAC6 is predominantly localized in the cytoplasm and has several specific nonhistone substrates, such as α-tubulin, cortactin, Hsp90, tau and peroxiredoxins. Accumulating evidence reveals that targeting HDAC6 may serve as a promising therapeutic strategy for the treatment of cancers, neurological disorders and immune diseases, making the development of HDAC6 inhibitors particularly attractive. Recently, multitarget drug design and proteolysis targeting chimera technology have also been applied in the discovery of novel small molecular modulators targeting HDAC6. In this review, we briefly describe the structural features and biological functions of HDAC6 and discuss the recent advances in HDAC6 modulators, including selective inhibitors, chimeric inhibitors and proteolysis targeting chimeras for multiple therapeutic purposes.

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Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma

Cited by 19 publications

References 30 publications

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

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