FL118, acting as a ‘molecular glue degrader’, binds to, dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c‐Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy

Abstract

By acting as a 'molecular glue degrader', FL118 directly binds to and functionally dephosphorylates and degrades the multifunctional master regulator DDX5 through the proteasome degradation pathway without decreasing DDX5 mRNA.• FL118 indirectly controls DDX5 downstream targets to inhibit cancer initiation, development, metastasis, recurrence and treatment resistance with high efficacy as demonstrated in this study using human colorectal cancer/pancreatic ductal adenocarcinoma cell and tumour models.

Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

“…In this regard, using the small-molecule drug FL118 affinity column purification of cancer cell lysate proteins, followed by mass spectrometry analyses, Ling et al identified that the DDX5 protein is the direct biochemical target of FL118. These authors demonstrated that FL118 acting as an MG degrader strongly binds to, dephosphorylates, and degrades DDX5 oncoprotein via proteasome degradation pathway, without decreasing DDX5 mRNA [ 49 ]. These studies further revealed that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins including survivin, Mcl-1, XIAP, cIAP2, c-Myc, and mutant Kras (mKras) [ 49 ].…”

“…These authors demonstrated that FL118 acting as an MG degrader strongly binds to, dephosphorylates, and degrades DDX5 oncoprotein via proteasome degradation pathway, without decreasing DDX5 mRNA [ 49 ]. These studies further revealed that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins including survivin, Mcl-1, XIAP, cIAP2, c-Myc, and mutant Kras (mKras) [ 49 ]. Pancreatic ductal adenocarcinoma (PDAC) cells with DDX5 knockout by vector-free Crispr technology are resistant to FL118 treatment [ 49 ], indicating DDX5 is a bona fide FL118 target.…”

“…These studies further revealed that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins including survivin, Mcl-1, XIAP, cIAP2, c-Myc, and mutant Kras (mKras) [ 49 ]. Pancreatic ductal adenocarcinoma (PDAC) cells with DDX5 knockout by vector-free Crispr technology are resistant to FL118 treatment [ 49 ], indicating DDX5 is a bona fide FL118 target. Importantly, human tumor animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and colorectal cancer (CRC) tumors that have a high expression of DDX5, while FL118 exhibits less effectiveness for PDAC and CRC tumors with low DDX5 expression [ 49 ].…”

“…Pancreatic ductal adenocarcinoma (PDAC) cells with DDX5 knockout by vector-free Crispr technology are resistant to FL118 treatment [ 49 ], indicating DDX5 is a bona fide FL118 target. Importantly, human tumor animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and colorectal cancer (CRC) tumors that have a high expression of DDX5, while FL118 exhibits less effectiveness for PDAC and CRC tumors with low DDX5 expression [ 49 ]. However, it is currently unknown which protein(s) and protein complex, as well as which ubiquitin regulators are involved in the dephosphorylation, ubiquitination, and degradation of DDX5 by FL118.…”

“…However, it is currently unknown which protein(s) and protein complex, as well as which ubiquitin regulators are involved in the dephosphorylation, ubiquitination, and degradation of DDX5 by FL118. Nevertheless, based on the literature-documented function of DDX5 plus the new discoveries related to FL118 and DDX5 in our paper [ 49 ], we outlined a graphical abstract to explain why FL118 has exceptional antitumor activity ( Figure 11 ).…”