Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth

Wan，Pui Ki1,2; Tong，Ka Chung1,2; Lok，Chun Nam1,2; Zhang，Chunlei1,2; Chang，Xiao Yong3; Sze，Kong Hung4; Tsai Wong，Alice Sze5; Che，Chi Ming1,2

2021-04-27

10.1073/pnas.2025806118

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   影响因子和分区

0027-8424

1091-6490

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= N-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.

Antimetastasis Metabolism N-heterocyclic carbene Platinum Vimentin

SCI

英语

NI论文

其他

Innovation and Technology Fund[ITS/488/18]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000672579000009

NATL ACAD SCIENCES

BIOLOGY & BIOCHEMISTRY;CLINICAL MEDICINE;MULTIDISCIPLINARY;PLANT & ANIMAL SCIENCE;ENVIRONMENT/ECOLOGY;SOCIAL SCIENCES, GENERAL;MICROBIOLOGY;ECONOMICS BUSINESS;IMMUNOLOGY;MATERIALS SCIENCE;MATHEMATICS;SPACE SCIENCE;MOLECULAR BIOLOGY & GENETICS;PHARMACOLOGY & TOXICOLOGY;CHEMISTRY;PSYCHIATRY/PSYCHOLOGY;NEUROSCIENCE & BEHAVIOR;PHYSICS;GEOSCIENCES;AGRICULTURAL SCIENCES;ENGINEERING

2-s2.0-85105281911

Scopus

1.State Key Laboratory of Synthetic Chemistry,Department of Chemistry,The University of Hong Kong,Hong Kong,Hong Kong
2.Laboratory for Synthetic Chemistry and Chemical Biology,Hong Kong,Hong Kong
3.Department of Chemistry,Southern University of Science and Technology of China,Shenzhen, Guangdong,518055,China
4.Department of Microbiology,The University of Hong Kong,Hong Kong,Hong Kong
5.School of Biological Sciences,The University of Hong Kong,Hong Kong,Hong Kong

Wan，Pui Ki,Tong，Ka Chung,Lok，Chun Nam,et al. Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2021,118(17).

Wan，Pui Ki.,Tong，Ka Chung.,Lok，Chun Nam.,Zhang，Chunlei.,Chang，Xiao Yong.,...&Che，Chi Ming.(2021).Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,118(17).

Wan，Pui Ki,et al."Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118.17(2021).