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.
- 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: [email protected].
- 5. School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China. Electronic address: [email protected].
- 6. School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: [email protected].
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.