Programmable Modular Assembly of Homochiral Ir(III)-Metallohelices to Reverse Metallodrug Resistance by Inhibiting CDK1

Abstract

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-H_bpy and Δ₂R₄-H_bpy, Δ₂S₄-H_bpy and Λ₂R₄-H_bpy) functionalized with flexible dithiourea linkages. The resulting homochiral metallohelices exhibited significant chirality-dependent photocytotoxicities, and the enhanced structural compatibility of Δ₂S₄-H_bpy with 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-H_bpy achieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT-8/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.