A novel photocaged B-RafV600E inhibitor toward precise melanoma treatment

Zhiyuan Chen; Ran Ke; Zhiqiang Song; Yang Zhou; Xiaomei Ren; Weixue Huang; Zhen Wang; Ke Ding

doi:10.1016/j.bmcl.2022.128683

A novel photocaged B-Raf^V600E inhibitor toward precise melanoma treatment

Bioorg Med Chem Lett. 2022 May 15:64:128683. doi: 10.1016/j.bmcl.2022.128683. Epub 2022 Mar 17.

Authors

Zhiyuan Chen¹, Ran Ke¹, Zhiqiang Song¹, Yang Zhou², Xiaomei Ren¹, Weixue Huang¹, Zhen Wang³, Ke Ding⁴

Affiliations

¹ State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Ling Ling Road, Shanghai 200032, PR China.
² International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China.
³ State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Ling Ling Road, Shanghai 200032, PR China. Electronic address: wangz@sioc.ac.cn.
⁴ State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Ling Ling Road, Shanghai 200032, PR China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China; The First Affiliated Hospital (Huaqiao Hospital), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China; Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, PR China. Electronic address: dingk@sioc.ac.cn.

PMID: 35307569
DOI: 10.1016/j.bmcl.2022.128683

Abstract

Photoinduced drug release can reduce systemic side effects by releasing active drugs with high spatiotemporal accuracy, representing a promising strategy for precise cancer therapy. Here we designed and synthesized a novel photocaged B-Raf^V600E inhibitor 2, which, upon UV irradiation, could release a potent B-Raf^V600E inhibitor 1. Accordingly, once activated by the UV light, compound 2 could potently inhibit the proliferation of melanoma cells bearing B-Raf^V600E mutant while sparing melanoma cells expressing wild-type B-Raf, and could dose-dependently suppress the activation of the MAPK signaling pathway. Notably, the UV-mediated active component release and the resulting antiproliferative effects of compound 2 could be recapitulated when exposed to the sunlight, greatly enhancing its practicality. This photocaged B-Raf^V600E inhibitor 2 might serve as a novel therapeutic agent toward precise melanoma treatment.

Keywords: Melanoma; Photocaged B-Raf(V600E) inhibitor; Photoinduced drug release; Precise treatment.

Publication types

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

MeSH terms

Cell Line, Tumor
Cell Proliferation
Humans
MAP Kinase Signaling System
Melanoma* / drug therapy
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins B-raf
Signal Transduction

Substances

Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf