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

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

  • Bioorg Med Chem Lett. 2019 Feb 1;29(3):349-352. doi: 10.1016/j.bmcl.2018.12.052.
Ruolan Zhou 1,  Shaoyu Fang 1,  Minmin Zhang 2,  Qingsen Zhang 3,  Jian Hu 3,  Mingping Wang 3,  Chongqing Wang 3,  Ju Zhu 3,  Aijun Shen 4,  Xin Chen 5,  Canhui Zheng 6
Affiliations

Affiliations

  • 1 School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 4 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: shenaj@simm.ac.cn.
  • 5 School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China. Electronic address: chenxin_0001@126.com.
  • 6 School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: canhuizheng@smmu.edu.cn.
PMID: 30594434 DOI: 10.1016/j.bmcl.2018.12.052
Abstract

Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.

Keywords

Anti-tumor agents; Bcl-2 inhibitors; Dualtarget inhibitors; HDAC inhibitors; HDAC6 inhibitors; Multiple myeloma.

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