title: Identification of a small molecule that downregulates MITF expression and mediates antimelanoma activity in vitro.
abstract: Melanoma is a type of cancer arising from the melanocytes, which are the cells that make up the pigment melanin and are derived from the neural crest. There is no particularly effective therapy once the disease is metastatic, highlighting the need for discovery of novel potent agents. In this investigation, we adopted a zebrafish embryonic pigmentation model to identify antimelanoma agents by screening an in-house small molecule library. With this assay, we found that a small molecule compound, SKLB226, blocked zebrafish pigmentation and pigment cell migration. Mechanism of action studies showed that SKLB226 downregulated MITF mRNA level in both zebrafish embryos and mammalian melanoma cells. Further studies showed that it could efficiently suppress the viability and migration of mammalian melanoma cells. In summary, SKLB226 can be used as a chemical tool to study melanocyte development as well as an antimelanoma lead compound that should be subjected to further structural optimization.
authors.affiliation: aState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University bState Key Laboratory Breeding Base of Systematic Research Development and Utilization of Chinese Medicine Resources, Sichuan Province and Ministry of Science and Technology, Chengdu, Sichuan cDepartment of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Cheng
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yang
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Shang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Qi-Zheng
authors.initials: QZ
authors.lastname: Sun
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Cao
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yao
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D051739:Microphthalmia-Associated Transcription Factor; D054852:Small Molecule Libraries