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.

中文翻译：

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同手性 Ir（III） - 金属螺旋的可编程模块化组装，通过抑制 CDK1 逆转金属药物耐药性


耐药是癌症复发和预后不良的主要原因。靶向耐药特异性蛋白的抑制剂的创新设计和合成是非常可取的。然而，在精确调整它们的构象和立体化学以适应靶蛋白的手性区域方面仍然存在挑战。在此，使用逐步可编程的模块化组装方法，我们精确设计了两对同手性双核 Ir（III） 金属螺旋（Λ2S4-Hbpy 和 Δ2R4-Hbpy、Δ2S4-Hbpy 和 Λ2R4-Hbpy），具有灵活的二硫脲键。所得的同手性金属螺旋体表现出显着的手性依赖性光细胞毒性，并且 Δ2S4-Hbpy与靶细胞周期蛋白依赖性激酶 1 （CDK1） 增强的结构相容性有助于其卓越的光动力治疗疗效，达到 2.3×104 的出色光细胞毒性指数 （PI） 值。有趣的是，作为奥沙利铂耐药发展的关键介质，Δ2S4-Hbpy靶向 CDK1 增强了奥沙利铂耐药 HCT8/L 细胞的细胞摄取、抗癌活性和肿瘤介导的细胞死亡。包括蛋白质组学分析和 CDK1 基因沉默在内的机制研究证实了手性选择性 CDK1 靶向在逆转金属耐药性中的关键作用。本研究引入了一个很有前途的平台，用于构建和定制具有精确构象和立体化学的柔性金属螺旋，以靶向耐药特异性蛋白质，为金属药物的设计能力提供创新见解以克服耐药性。