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

Abstract

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.

Two-Photon Photodegradation of E3 Ubiquitin Ligase Cereblon by a Ru(II) Complex: Inducing Ferroptosis in Cisplatin-Resistant Tumor Cells

“…The couple of Ru-Poma and CRBN proteins were conducted using cellular thermal shift assay (CETSA). The observed stability of a protein is altered when ligands bind, which results in a shift in the melting temperature ( T m ). , In Figure A, the immunoblot results showed that the abundance of CRBN protein in the A549R cell lysate decreased with increasing temperatures (55–75 °C). Differently, when A549R cells were pretreated with Ru-Poma (5 μM) for 6 h, the lysate showed a greater abundance of CRBN protein than the control group, suggesting Ru-Poma -dependent stabilization.…”

“…The 1 O 2 yield measurement was performed according to the previous report . For the electron paramagnetic resonance (EPR) assay, TEMP was used for trapping 1 O 2 as the reference suggested . The concentration of TEMP was 25 mM.…”

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

“…This approach holds promise in enhancing the efficacy of targeting Mcl-1 while minimizing off-target effects. Furthermore, this method can be extended to target other mitochondrial proteins . Compared to other Mcl-1 orthosteric inhibitors, metal complexes can improve cell distribution and enhance mitochondrial membrane permeability.…”

Anticancer mechanisms of β‐carbolines

“…Over past years, βcarbolines in association with different metals such as ruthenium (II) (Zhu et al, 2023), platinum(II) (Lu et al, 2023), copper(II) (Du et al, 2023), cobalt(II) (Momeni et al, 2022) and nickel(II) (Abdolmaleki et al, 2017) were discovered as a potent anticancer agent. The use of biologically active organometallic compounds and their derivatives attracted many researchers for advancement of cancer treatment (Kumar et al, 2017).…”