Novel Anticancer Agents Based on Targeting the Trimer Interface of the PRL Phosphatase.
Phosphatase of regenerating liver (PRL) oncoproteins are phosphatases overexpressed in numerous types of human cancer. Elevated levels of PRL associate with metastasis and poor clinical outcomes. In principle, PRL phosphatases offer appealing therapeutic targets, but they remain underexplored due to the lack of specific chemical probes. In this study, we address this issue by exploiting a unique property of PRL phosphatases, namely, that they may function as homotrimers. Starting from a sequential structure-based virtual screening and medicinal chemistry strategy, we identified Cmpd-43 and several analogs that disrupt PRL1 trimerization. Biochemical and structural analyses demonstrate that Cmpd-43 and its close analogs directly bind the PRL1 trimer interface and obstruct PRL1 trimerization. Cmpd-43 also specifically blocks the PRL1-induced cell proliferation and migration through attenuation of both ERK1/2 and Akt activity. Importantly, Cmpd-43 exerted potent anticancer activity both in vitro and in vivo in a murine xenograft model of melanoma. Our results validate a trimerization-dependent signaling mechanism for PRL and offer proof of concept for trimerization inhibitors as candidate therapeutics to treat PRL-driven cancers. Cancer Res; 76(16); 4805-15. ©2016 AACR.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, West Lafayette, Indiana. Department of Chemistry, Purdue University, West Lafayette, Indiana.
Yunpeng
Y
Bai
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, West Lafayette, Indiana. Department of Chemistry, Purdue University, West Lafayette, Indiana.
Zhi-Hong
ZH
Yu
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Sijiu
S
Liu
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Lujuan
L
Zhang
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, West Lafayette, Indiana. Department of Chemistry, Purdue University, West Lafayette, Indiana.
Ruo-Yu
RY
Zhang
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Li-Fan
LF
Zeng
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, West Lafayette, Indiana. Department of Chemistry, Purdue University, West Lafayette, Indiana.
Sheng
S
Zhang
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, West Lafayette, Indiana. Department of Chemistry, Purdue University, West Lafayette, Indiana. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. zhang-zy@purdue.edu.
Zhong-Yin
ZY
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases