Discovery of a first-in-class degrader for microphthalmia-associated transcription factor (MITF).

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.