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Discovery of a first-in-class degrader for microphthalmia-associated transcription factor (MITF)
Weizhong Shen1, Hanming Yang2, Yihan Chen1
1State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China; University of Chinese Academy of Sciences, #1 Yanxihu Road, Huairou District, Beijing, 101408, China.
Abstract:
Microphthalmia-associated transcription factor (MITF) is a transcription factor that plays a central role in the pathogenesis, progression, and drug resistance of malignant melanoma. However, MITF has historically been viewed as a challenging drug target, largely due to a lack of deep, well-defined pockets amenable to traditional small-molecule inhibition. In this study, we present the discovery of WZS0347, a first-in-class proteolysis targeting chimera (PROTAC) designed to target MITF for degradation. WZS0347 potently reduced MITF protein levels in several melanoma cell lines, including B16F10, A375 and GAK. Mechanistic investigation confirmed that the degradation was mediated by a cereblon-dependent ubiquitin-proteasome pathway. Consequently, WZS0347 treatment led to the downregulation of MITF downstream target genes and significantly inhibited cancer cell colony formation and migration capacity.
Insights
Researchers developed WZS0347, a novel PROTAC, to degrade the Microphthalmia-associated transcription factor (MITF) in melanoma. This approach effectively reduced MITF levels, inhibiting cancer cell growth and migration.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Microphthalmia-associated transcription factor (MITF) is crucial in melanoma pathogenesis, progression, and drug resistance.
- MITF presents a challenge as a drug target due to its lack of suitable binding pockets for traditional inhibitors.
Purpose of the Study:
- To discover and characterize a novel therapeutic agent targeting MITF for degradation in malignant melanoma.
- To evaluate the efficacy of a proteolysis targeting chimera (PROTAC) designed to degrade MITF.
Main Methods:
- Discovery and design of WZS0347, a first-in-class PROTAC targeting MITF.
- Assessment of MITF protein level reduction in melanoma cell lines (B16F10, A375, GAK).
- Mechanistic studies involving the ubiquitin-proteasome pathway and cereblon dependency.
Main Results:
- WZS0347 demonstrated potent reduction of MITF protein levels across multiple melanoma cell lines.
- Degradation was confirmed to be mediated by the cereblon-dependent ubiquitin-proteasome pathway.
- Treatment with WZS0347 led to downregulation of MITF target genes and significant inhibition of melanoma cell colony formation and migration.
Conclusions:
- WZS0347 represents a novel PROTAC strategy for targeting MITF degradation in melanoma.
- This approach effectively inhibits melanoma progression by targeting a key transcription factor.
- The findings support the potential of PROTACs as a viable therapeutic modality for challenging targets like MITF in cancer.
