Design, synthesis and biological evaluation of tyrosine derivatives as Mcl-1 inhibitors

Abstract

The upregulation of the protein myeloid cell leukemia-1 (Mcl-1) is closely associated with various human cancers, which can result in the evasion of apoptosis and a low survival rate. Therefore, developing Mcl-1 inhibitors has become a promising paradigm for cancer therapy. Herein, we designed and synthesized a novel series of tyrosine derivatives, among which compounds 5g, 6l and 6c exhibited very high binding affinity to Mcl-1 with K_i values of 0.18, 0.27 and 0.23 μM, respectively. Interestingly, compound 6l showed not only potent activity against Mcl-1 but also considerable selectivity over Bcl-2 and Bcl-xL, which was rationalized by molecular docking and fragment-centric topographical mapping (FCTM). It is worth noting that compounds 5g, 6l and 6c displayed potent antiproliferative activity against several cancer cell lines and could induce apoptosis of KM3 and HepG2 cells in a dose-dependent manner.

Keywords: Apoptosis; Cancer; Mcl-1 inhibitors; Tyrosine derivatives.