Platinum-Based Mcl‑1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199

Discovery of small molecule inhibitors targeting Mcl-1
(Myeloid
cell leukemia 1) confronts many challenges. Based on the fact that
Mcl-1 is mainly localized in mitochondria, we propose a new strategy
of targeting mitochondria to improve the binding efficiency of Mcl-1
inhibitors. We report the discovery of complex 9, the
first mitochondrial targeting platinum-based inhibitor of Mcl-1, which
selectively binds to Mcl-1 with high binding affinity. Complex 9 was mainly concentrated in the mitochondria of tumor cells
which led to an enhanced antitumor efficacy. Complex 9 induced Bax/Bak-dependent apoptosis in LP-1 cells and synergized
with ABT-199 to kill ABT-199 resistant cells in multiple cancer models.
Complex 9 was effective and tolerable as a single agent
or in combination with ABT-199 in mouse models. This research work
demonstrated that developing mitochondria-targeting Mcl-1 inhibitors
is a new potentially efficient strategy for tumor therapy.