2. Academic Validation
  3. A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy

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

  • Cell Res. 2023 Jan;33(1):55-70. doi: 10.1038/s41422-022-00744-5.
Zaizhou Liu # 1,  Kaige Chen # 2 3,  Jun Dai 4 5,  Peng Xu 1 6,  Wei Sun 7,  Wanlin Liu 7,  Zhixin Zhao 1,  Steven P Bennett 8,  Peifeng Li 1,  Tiancheng Ma 1,  Yuqi Lin 1,  Akinori Kawakami 4,  Jing Yu 1,  Fei Wang 1,  Chunxi Wang 1,  Miao Li 1,  Peter Chase 8 9,  Peter Hodder 8 10,  Timothy P Spicer 8,  Louis Scampavia 8,  Chunyang Cao 1,  Lifeng Pan 1 6,  Jiajia Dong 1,  Yong Chen 11,  Biao Yu 12 13,  Min Guo 14 15,  Pengfei Fang 16 17,  David E Fisher 18,  Jing Wang 19 20
Affiliations

Affiliations

  • 1 State 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.
  • 2 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China.
  • 3 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
  • 4 Department of Dermatology, Cutaneous Biology Research Center, Mass. General Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
  • 6 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 7 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 8 Scripps Research, Jupiter, FL, USA.
  • 9 BMS Inc., Lawrenceville, NJ, USA.
  • 10 Amgen Inc., Thousand Oaks, CA, USA.
  • 11 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. chenyong@fudan.edu.cn.
  • 12 State 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. byu@sioc.ac.cn.
  • 13 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China. byu@sioc.ac.cn.
  • 14 State 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. guomin@healthcodon.com.
  • 15 Kangma-Healthcode Biotech Co., Ltd., Shanghai, China. guomin@healthcodon.com.
  • 16 State 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. fangpengfei@sioc.ac.cn.
  • 17 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China. fangpengfei@sioc.ac.cn.
  • 18 Department of Dermatology, Cutaneous Biology Research Center, Mass. General Hospital, Harvard Medical School, Boston, MA, USA. DFISHER3@mgh.harvard.edu.
  • 19 State 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. Jwang@sioc.ac.cn.
  • 20 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China. Jwang@sioc.ac.cn.
  • # Contributed equally.
PMID: 36588115 DOI: 10.1038/s41422-022-00744-5
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156483
    99.89%, MITF Inhibitor