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

Cell Research volume 33, pages 55–70 (2023)Cite this article

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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.

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Fig. 1: MITF has a distinct dynamic leucine zipper.
Fig. 2: MITF loss-of-function mutations reveal the critical role of the HLH-LZ region.
Fig. 3: Loss-of-function mutations in HLH-LZ disrupt MITF dimer formation.
Fig. 4: High-throughput screening identifies a MITF dimer disruptor TT-012.
Fig. 5: TT-012 suppresses MITF activity and function in melanoma cells.
Fig. 6: TT-012 inhibits MITF-high melanoma growth in vitro and in vivo.
Fig. 7: TT-012 has tolerable toxicity to liver and immune cells in mouse model.

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Acknowledgements

The study is supported by the Lingang Laboratory (LG-QS-202205-11 to J.W. and W.S.); the National Natural Science Foundation of China (21977108 and 21778067 to J.W.; 21778064 and 21977107 to P.F.; and 21621002 to B.Y.); the Shanghai Science and Technology Committee (20S11901100 to J.W. and 19411951700 to Y.C.); the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000 to J.W., P.F. and B.Y.); One-hundred Talents Program of Chinese Academy of Sciences (to J.W.); the State Key Laboratory of Bioorganic and Natural Products Chemistry (to J.W., P.F. and B.Y.); a 1000-talent young investigator award (to P.F.); the K. C. Wong Education Foundation (to B.Y.); NIH grants (GM100136 to M.G.; 2P01 CA163222-06; 5R01 AR043369-23; 5R01CA222871-02 and 5R01AR072304-03 to D.E.F.) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.E.F.). The authors also gratefully acknowledge technical supports from Chemical Biology Core Facility at Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; Fudan University Shanghai Cancer Center Laboratory Animal Science. The authors also grateful acknowledge Prof. Jun Wang for the support on the mice experiments and Dr. Tom Powell and Dr. Tamar Babilla Propp for expert assistance with paper preparation.

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Author notes

  1. Kaige Chen

    Present address: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China

  2. Peter Chase

    Present address: BMS Inc., Lawrenceville, NJ, USA

  3. Peter Hodder

    Present address: Amgen Inc., Thousand Oaks, CA, USA

  4. These authors contributed equally: Zaizhou Liu, Kaige Chen.

Authors and 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

    Zaizhou Liu, Peng Xu, Zhixin Zhao, Peifeng Li, Tiancheng Ma, Yuqi Lin, Jing Yu, Fei Wang, Chunxi Wang, Miao Li, Chunyang Cao, Lifeng Pan, Jiajia Dong, Biao Yu, Min Guo, Pengfei Fang & Jing Wang

  2. School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China

    Kaige Chen

  3. Department of Dermatology, Cutaneous Biology Research Center, Mass. General Hospital, Harvard Medical School, Boston, MA, USA

    Jun Dai, Akinori Kawakami & David E. Fisher

  4. School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA

    Jun Dai

  5. School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China

    Peng Xu, Lifeng Pan, Biao Yu, Pengfei Fang & Jing Wang

  6. Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Wei Sun, Wanlin Liu & Yong Chen

  7. Scripps Research, Jupiter, FL, USA

    Steven P. Bennett, Peter Chase, Peter Hodder, Timothy P. Spicer & Louis Scampavia

  8. Kangma-Healthcode Biotech Co., Ltd., Shanghai, China

    Min Guo

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  1. Zaizhou Liu
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Contributions

J.W., D.E.F., P.F., M.G., B.Y., and Y.C. provided funding, designed the study, participated in data analysis, drafted and revised the manuscript. Z.L., K.C., J. Dai, P.X., W.S., W.L., Z.Z., S.P.B., P.L., T.M., Y.L., A.K., J.Y., F.W., C.W., M.L., and P.C. designed the study, performed experiments, analyzed the data. P.H., T.P.S., L.S., C.C., L.P., and J.Dong participated in the experiments and/or revised the paper.

Corresponding authors

Correspondence to Yong Chen, Biao Yu, Min Guo, Pengfei Fang, David E. Fisher or Jing Wang.

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Competing interests

Dr. D.E.F. has a financial interest in Soltego Inc., a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. Dr. D.E.F. interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their competing interests policies.

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Liu, Z., Chen, K., Dai, J. et al. A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy. Cell Res 33, 55–70 (2023). https://doi.org/10.1038/s41422-022-00744-5

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