Targeting the Lin28/let-7 Axis with Compounds to Regulate Transcriptional Control in Cancer.

Abstract

Lin28 is a pivotal RNA-binding protein that regulates the biogenesis of let-7 microRNAs, which play a crucial role in the post-transcriptional regulation of oncogenes in cancer. The Lin28/let-7 axis is integral to the regulation of key cellular processes such as proliferation, differentiation, and apoptosis. Lin28 promotes the upregulation of oncogenes, including MYC, RAS, and HMGA2, by inhibiting the maturation of let-7, thereby facilitating tumor initiation, progression, and metastasis. Consequently, targeting the Lin28/let-7 interaction has emerged as a promising therapeutic strategy, particularly for malignancies that lack specific molecular targets. This approach holds potential for downregulating oncogene expression and inhibiting tumor progression. Through a comprehensive review of the literature, this article classifies Lin28/let-7 inhibitors into three categories: CSD/ZKD inhibitors, non-CSD/ZKD inhibitors, and let-7 restorers. CSD/ZKD inhibitors, such as TPEN and KCB3602, function by binding to the CSD or ZKD domains of Lin28, thereby inhibiting its activity. Non- CSD/ZKD inhibitors, including compounds like C1632 and Simvastatin, have been identified as molecules that can reduce Lin28 activity, though their binding sites remain unknown. Let-7 restorers, on the other hand, do not directly target Lin28 but instead work indirectly by modulating the activity of associated molecules, such as Zcchc11 and Zcchc6, thereby promoting the restoration of let-7 expression levels. Notable examples of these include IPA-3 and FPA124. This review summarizes recent advances in the development of Lin28/let-7 inhibitors and their therapeutic potential, providing an important reference for ongoing research on Lin28 inhibitors in cancer therapy.