State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
Laboratory for Synthetic Chemistry and Chemical Biology, Hong Kong, China.
Proc Natl Acad Sci U S A. 2021 Apr 27;118(17). doi: 10.1073/pnas.2025806118.
Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [Pt(C^N^N)(NHC)]PF (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= -heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.
波形蛋白是一种细胞骨架中间丝蛋白，在肿瘤的发生、发展和转移中起着关键作用，其在侵袭性癌症中的过表达预示着预后不良。本文描述了一种高效的抗肿瘤和抗转移金属配合物[Pt(C^N^N)(NHC)]PF（Pt1a；HC^N^N=6-苯基-2,2'-联吡啶；NHC=-杂环卡宾），它通过与独特的正交结构支架的非共价结合相互作用与波形蛋白结合。Pt1a 显示出与表面等离子体共振测量的解离常数为 1.06 µM 的波形蛋白结合亲和力，并适合与波形蛋白的卷曲螺旋之间的口袋结合，具有多个疏水相互作用。它在细胞内与波形蛋白结合，破坏波形蛋白细胞骨架，降低肿瘤中的波形蛋白表达，抑制不同小鼠模型中的异种移植物生长和转移，并且具有良好的耐受性，这归因于生物转化为毒性较小且可经肾脏清除的铂(II)物种。我们的研究揭示了铂(II)‒NHC 配合物作为有效靶向化疗治疗转移性和顺铂耐药性癌症的实际治疗潜力。
