Drug resistance is a major cause of cancer recurrence and poor prognosis. The innovative design and synthesis of inhibitors to target drug-resistance-specific proteins is highly desirable. However, challenges remain in precisely adjusting their conformation and stereochemistry to adapt the chiral regions of target proteins. Herein, using a stepwise programmable modular assembly approach, we precisely engineered two pairs of homochiral dinuclear Ir(III) metallohelices (Λ2S4-Hbpy and Δ2R4-Hbpy, Δ2S4-Hbpy and Λ2R4-Hbpy) functionalized with flexible dithiourea linkages. The resulting homochiral metallohelices exhibited significant chirality-dependent photocytotoxicities, and the enhanced structural compatibility ofΔ2S4-Hbpywith the target cyclin-dependent kinase 1 (CDK1) contributed to its superior photodynamic therapy efficacy, achieving an outstanding photocytotoxicity index (PI) value of 2.3×104. Interestingly, emerging as a critical mediator in the development of oxaliplatin resistance, CDK1 targeting by Δ2S4-Hbpyachieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT8/L cells. Mechanistic investigations, including proteomic profiling and CDK1 gene silencing, confirmed the pivotal role of chirality-selective CDK1 targeting in reversing metallodrug resistance. This study introduces a promising platform for constructing and customizing flexible metallohelices with precise conformation and stereochemistry to target drug-resistance-specific proteins, offering innovative insights into the designability of metallodrugs to overcome drug resistance.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/anie.202419292 | DOI Listing |
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!