Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis, anticancer activity and B-Raf degradation
- Bioorg Chem. 2019 Jun;87:191-199. doi: 10.1016/j.bioorg.2019.03.035.
- 1. Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
- 2. Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China. Electronic address: [email protected].
As the first intracellular signaling molecule and the most frequently mutated oncogene, B-Raf represents an important target in Cancer therapy. Here we report several pomalidomide hybrids acting as proteolysis targeting chimeras (PROTACs) for the degradation of B-Raf. Due to its high expression of B-Raf, MCF-7 cells are sensitive to these compounds. Among them, compound 2 can effectively kill Cancer cells via inducing cells Apoptosis. As a B-Raf Degrader, compound 2 can accelerate the degradation of B-Raf by recruiting ubiquitin-proteasome system, and further affects the expression of Mcl-1, a downstream protein of B-Raf. The Anticancer mechanism of compound 2 is quite different from its mother compound and Cancer cells seem to be more sensitive to the degrader, hinting that degradation of B-Raf by PROTAC is a potential way for Cancer treatment.