Chemoproteomics Reveals the Antiproliferative Potential of Parkinson's Disease Kinase Inhibitor LRRK2-IN-1 by Targeting PCNA Protein

Weichao Li; Yiqing Zhou; Guanghui Tang; Nai-Kei Wong; Mengquan Yang; Dan Tan; Youli Xiao

doi:10.1021/acs.molpharmaceut.8b00325

Chemoproteomics Reveals the Antiproliferative Potential of Parkinson's Disease Kinase Inhibitor LRRK2-IN-1 by Targeting PCNA Protein

Mol Pharm. 2018 Aug 6;15(8):3252-3259. doi: 10.1021/acs.molpharmaceut.8b00325. Epub 2018 Jul 24.

Authors

Weichao Li¹, Yiqing Zhou¹, Guanghui Tang², Nai-Kei Wong³, Mengquan Yang^{1

4}, Dan Tan⁵, Youli Xiao^{1

4}

Affiliations

¹ CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences , Chinese Academy of Sciences , Shanghai 200032 , China.
² School of Chemical Biology and Biotechnology , Peking University Shenzhen Graduate School , Shenzhen 518055 , China.
³ State Key Discipline of Infection Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital , Shenzhen University , Shenzhen 518112 , China.
⁴ University of Chinese Academy of Sciences , Beijing 100039 , China.
⁵ Ruijin Hospital , Shanghai Jiaotong University School of Medicine , Shanghai 200025 , China.

PMID: 29993254
DOI: 10.1021/acs.molpharmaceut.8b00325

Abstract

LRRK2-IN-1, one of the first selective inhibitors of leucine-rich repeat kinase 2 (LRRK2), was serendipitously found to exhibit potent antiproliferative activity in several types of human cancer cells. In this study, we employed a chemoproteomic strategy utilizing a photoaffinity probe to identify the cellular target(s) of LRRK2-IN-1 underlying its anticancer activity. LRRK2-IN-1 was found to induce cell cycle arrest as well as cancer cell death by specifically binding to human proliferating cell nuclear antigen (PCNA) in cancer cells. Our current findings suggest the potential of LRRK2-IN-1 as a novel pharmacological molecule for scrutinizing cell physiology and furnish a logical foundation for the future development of therapeutic reagents for cancer.

Keywords: LRRK2-IN-1; PCNA; antiproliferative; chemical proteomics; click chemistry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiparkinson Agents / pharmacology*
Benzodiazepinones / pharmacology*
Cell Proliferation / drug effects
Drug Repositioning
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Jurkat Cells
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors
Molecular Probes / chemistry
Parkinson Disease / drug therapy
Photoaffinity Labels / chemistry
Proliferating Cell Nuclear Antigen / metabolism*
Protein Kinase Inhibitors / pharmacology*
Proteomics / methods
Pyrimidines / pharmacology*

Substances

Antiparkinson Agents
Benzodiazepinones
LRRK2-IN1
Molecular Probes
PCNA protein, human
Photoaffinity Labels
Proliferating Cell Nuclear Antigen
Protein Kinase Inhibitors
Pyrimidines
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2