Targeted degradation of CD147 proteins in melanoma

Zhe Zhou; Jing Long; Yuan Wang; YaYun Li; Xu Zhang; Ling Tang; Qi Chang; Zhuo Chen; GaoYun Hu; Shuo Hu; QianBin Li; Cong Peng; Xiang Chen

doi:10.1016/j.bioorg.2020.104453

Targeted degradation of CD147 proteins in melanoma

Bioorg Chem. 2020 Dec:105:104453. doi: 10.1016/j.bioorg.2020.104453. Epub 2020 Nov 4.

Authors

Zhe Zhou¹, Jing Long¹, Yuan Wang², YaYun Li¹, Xu Zhang¹, Ling Tang¹, Qi Chang³, Zhuo Chen³, GaoYun Hu³, Shuo Hu⁴, QianBin Li⁵, Cong Peng⁶, Xiang Chen⁷

Affiliations

¹ The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
³ Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
⁴ Department of Nuclear Medicine, XiangYa Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan, China.
⁵ Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China. Electronic address: qbli@csu.edu.cn.
⁶ The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: pengcongxy@csu.edu.cn.
⁷ The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: chenxiangck@126.com.

PMID: 33197849
DOI: 10.1016/j.bioorg.2020.104453

Abstract

CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.

Keywords: CD147; Degradation; Melanoma; PROTAC; Pseudolaric Acid B.

Publication types

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

MeSH terms

Alkylation
Animals
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Basigin* / metabolism
Cell Line, Tumor
Cell Movement
Diterpenes* / chemical synthesis
Diterpenes* / pharmacology
Drug Screening Assays, Antitumor
Female
Humans
Melanoma* / drug therapy
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental
Proteolysis*
Wound Healing / drug effects

Substances

Antineoplastic Agents
Basigin
Diterpenes
pseudolaric acid B