1 research outputs found
Design, Synthesis, and Biological Evaluation of the First c‑Met/HDAC Inhibitors Based on Pyridazinone Derivatives
Simultaneous blockade of more than
one pathway is considered to be a promising approach to overcome the
low efficacy and acquired resistance of cancer therapies. Thus, a
novel series of c-Met/HDAC bifunctional inhibitors was designed and
synthesized by merging pharmacophores of c-Met and HDAC inhibitors.
The most potent compound, <b>2m</b>, inhibited c-Met kinase
and HDAC1, with IC<sub>50</sub> values of 0.71 and 38 nM, respectively,
and showed efficient antiproliferative activities against both EBC-1
and HCT-116 cells with greater potency than the reference drug Chidamide.
Western blot analysis revealed that compound <b>2m</b> inhibited
phosphorylation of c-Met and c-Met downstream signaling proteins and
increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent
manner. Our study presents novel compounds for the further exploration
of dual c-Met/HDAC pathway inhibition achieved with a single molecule