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A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy

Zaizhou Liu1,† , Kaige Chen2,9,† , Jun Dai3,4 , Peng Xu1,5 , Wei Sun6 , Wanlin Liu6 , Zhixin Zhao1 , Steven P. Bennett7 , Peifeng Li1 , Tiancheng Ma1 , Yuqi Lin1 , Akinori Kawakami3 , Jing Yu1 , Fei Wang1 , Chunxi Wang1 , Miao Li1 , Peter Chase7,10 , Peter Hodder7,11 , Timothy P. Spicer7 , Louis Scampavia7 , Chunyang Cao1 , Lifeng Pan1,5 , Jiajia Dong1 , Yong Chen6,* , Biao Yu1,5,* , Min Guo1,8,* , Pengfei Fang1,5,* , David E. Fisher3 , Jing Wang1,5

1State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
2School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China
3Department of Dermatology, Cutaneous Biology Research Center, Mass. General Hospital, Harvard Medical School, Boston, MA, USA
4School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
5School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
6Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
7Scripps Research, Jupiter, FL, USA
8Kangma-Healthcode Biotech Co., Ltd., Shanghai, China
9Present address: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
10Present address: BMS Inc., Lawrenceville, NJ, USA
11Present address: Amgen Inc., Thousand Oaks, CA, USA
These authors contributed equally: Zaizhou Liu, Kaige Chen
* Correspondence: Yong Chen(chenyong@fudan.edu.cn)Biao Yu(byu@sioc.ac.cn)Min Guo(guomin@healthcodon.com)Pengfei Fang(fangpengfei@sioc.ac.cn)

Microphthalmia transcription factor (MITF) regulates melanocyte development and is the “lineage-specific survival” oncogene of melanoma. MITF is essential for melanoma initiation, progression, and relapse and has been considered an important therapeutic target; however, direct inhibition of MITF through small molecules is considered impossible, due to the absence of a ligand-binding pocket for drug design. Here, our structural analyses show that the structure of MITF is hyperdynamic because of its out-of-register leucine zipper with a 3-residue insertion. The dynamic MITF is highly vulnerable to dimer-disrupting mutations, as we observed that MITF loss-of-function mutations in human Waardenburg syndrome type 2 A are frequently located on the dimer interface and disrupt the dimer forming ability accordingly. These observations suggest a unique opportunity to inhibit MITF with small molecules capable of disrupting the MITF dimer. From a high throughput screening against 654,650 compounds, we discovered compound TT-012, which specifically binds to dynamic MITF and destroys the latter’s dimer formation and DNA-binding ability. Using chromatin immunoprecipitation assay and RNA sequencing, we showed that TT-012 inhibits the transcriptional activity of MITF in B16F10 melanoma cells. In addition, TT-012 inhibits the growth of high-MITF melanoma cells, and inhibits the tumor growth and metastasis with tolerable toxicity to liver and immune cells in animal models. Together, this study demonstrates a unique hyperdynamic dimer interface in melanoma oncoprotein MITF, and reveals a novel approach to therapeutically suppress MITF activity.

https://doi.org/10.1038/s41422-022-00744-5

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