Figure 11.

FL118 mechanism of action (MOA). DDX5 is a multifunctional master regulator involved in (1) co-activation of transcription of many oncogenes through the direct interactions of different transcription factors (e.g., c-Myc) in the oncogenic gene promoters, (2) regulation of miRNA and pre-RNA splicing (e.g., U1, U2, U3, …, snRNP), and (3) ribosome biogenesis (e.g., 32S rRNA, pre-ribosome). The small-molecule drug FL118 directly binds to and functionally dephosphorylates and degrades DDX5 protein (without decreasing DDX5 mRNA) through the proteasome degradation pathway. This suggests that FL118 could glue both DDX5 and ubiquitin-involved protein stability/degradation regulators (i.e., FL118 acts as a “molecular glue degrader”). All the DDX5 downstream protein targets were known to be involved in cancer initiation, development, metastasis, recurrence, and treatment resistance. Therefore, indirectly blocking DDX5 downstream targets through direct dephosphorylation and degradation of DDX5 by FL118 could result in FL118 high antitumor efficacy as demonstrated in our recent study, which used human CRC and PDAC cell and tumor models [49].