黑色素细胞通过分泌黑色素使皮肤免受紫外线辐射伤害，是人体的直接保护防线。MITF是黑色素细胞分化、存活以及功能发挥的关键转录因子，也是恶性黑色素瘤最为重要的直系致癌基因。研发特异靶向抑制MITF的小分子化合物，是研究黑色素细胞生理病理过程的探针工具，同时具有治疗恶性黑色素瘤的重要潜在价值。本项目利用课题组独有的51个抑制MITF二体形成的活性小分子化合物，结合生化细胞实验和蛋白质晶体实验，考察活性小分子化合物对MITF的作用方式和作用能力，获得对MITF识别抑制起关键作用的化合物骨架和化学基团，并从分子水平理解其抑制机理。得到高效，特异靶向，机理明确的抑制MITF的小分子化合物探针，并考察其作为恶性黑色素瘤治疗的药用潜力。本项目的研究，从分子-生化-细胞多层面研究化合物与转录因子的作用机理，拓展了靶向转录因子的思路，为黑色素细胞生理病理研究提供分子探针工具和具有药用潜力的小分子化合物。

Melanocyte is the specialized pigment cell that synthesizes melanin and protects the skin, also the whole organism from UV exposure. Microphthalmia transcription factor, MITF, is a master regulator of melanocyte development, differentiation, migration and survival. MITF also plays essential oncogenic roles in melanoma formation, migration and drug resistance, and was identified as the lineage survival oncogene in malignant melanoma. Small molecular compounds specifically targeting MITF could work as probe to explore the pathological and pathogenic role of MITF in melanocyte and melanoma. And it also has potential ability to work as pharmacologic inhibitors for melanoma treatment. Here, we propose to explore the active pharmacore for effective MITF inhibition, based on 51-small molecular-compounds-collection with the ability to disrupt MITF dimer formation. With the comprehensive molecular and cellular information regarding the compound –MITF recognition and function, the active pharmacore would be optimized and explored for the potential ability to suppress melanoma cell growth. Except providing a useful molecular probe for melanocyte study, this work would expand the knowledge for targeting transcription factor with small molecular compound, and may offer novel therapeutic compounds for melanoma treatment.