In addition, the consequences of simultaneously degrading DDX5 and UbE2T proteins by the small-molecule dual molecular glue degrader FL118 in difficult-to-treat advanced cancers are presented.Specifically, this article reviews: (1) the roles of DDX5 and UbE2T in diverse cancer DNA repair pathways; (2) the physical binding relationship and potential functional roles of DDX5 in topoisomerase regulation; (3) the involvement of DDX5 in EZH2- and NANOG-associated prostate cancer stem cell (PCSC)-driven neuroendocrine prostate cancer (NEPC), castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC); (4) the contributions of DDX5 and UbE2T to inflammatory and immune regulation within the tumor microenvironment (TME); (5) FL118 as a small-molecule dual molecular glue degrader selectively targeting both DDX5 and UbE2T; (6) the high efficacy of FL118 against multiple difficult-to-treat advanced and metastatic cancers, including advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, Ewing sarcoma, ovarian cancer, and glioma/glioblastoma; (7) the resistance of ABCG2-expressing cancer cells to common anticancer agents but not to FL118; (8) the favorable pharmacokinetic and toxicology profiles of FL118 in mice, rats, and dogs; (9) the distinct functions of DDX5 in normal tissues, cells, and organs versus cancer; and (10) FL118 as a drug platform enabling the development of novel analogs and derivatives.Based on this review, we conclude that DDX5 and UbE2T represent superior anticancer therapeutic targets, and that the high efficacy of FL118 against multiple difficult-to-treat cancers is attributable to its function as a bona fide small-molecule dual molecular glue degrader that physically targets and degrades both DDX5 and UbE2T. Strikingly, this activity is observed regardless of the expression status of ABC transporter proteins, ABCG2/BCRP, ABCB1/Pgp/MDR1, and/or ABCC1/MRP1 in cancer cells.

Moreover, the small molecule inhibitor FL118 was able to disrupt this process by promoting DDX5 degradation, unveiling FL118 as a new potential antiviral drug. Our findings established a new functional axis of EBNA1/DDX5/BZLF1, adding to the knowledge about the role of EBNA1 in the regulation of EBV life cycle, particularly for lytic replication. The study also provided potential therapeutic strategy for EBV-associated epithelial tumors.

In contrast, during adipocyte differentiation, the helicase function of DDX5 is essential for glucocorticoid receptor transcriptional programs. Importantly, recent studies have identified the small-molecule compound FL118 as a potent DDX5 degrader, providing proof of concept that targeting DDX5 protein stability represents a promising therapeutic strategy.

In a subcutaneous tumor model, in which Ba/F3 cells expressing JAK2V617F and EpoR were transplanted into nude mice, oral administration of FL118 significantly reduced tumor growth and hepatosplenomegaly. Collectively, these findings establish DDX5 as a promising therapeutic target in MPNs and underscore the potential of FL118 as a treatment strategy for JAK2V617F-driven disease.

In A549 and AsPC-1 xenograft models, PDC-2 demonstrated superior tumor growth inhibition, reduced systemic toxicity, and enhanced tumor specificity compared to FL118. Pharmacokinetically, it enabled a sustained release of FL118, extending its half-life by 3.4-fold and promoting targeted tumor accumulation, positioning it as a promising therapeutic for lung and pancreatic cancers.

Herein, we present a novel camptothecin derivative named 9c, which exhibits impressive anti-NSCLC potency surpassing the widely recognized camptothecin analog FL118 through a novel mechanism. Importantly, it complemented the therapeutic advantages of the novel drug AMG510 for addressing KRAS-mutant NSCLC. Collectively, these findings position 9c as a promising candidate with innovative approaches to combat NSCLC.

P1, N=0, Withdrawn, Roswell Park Cancer Institute | N=84 --> 0 | Not yet recruiting --> Withdrawn

In vivo, Sac-CL2A-FL118 showed 130 % tumor growth inhibition (TGI) at 7 mg/kg in Trop2-expressing xenografts surpassing Trodelvy®. Pharmacokinetic evaluations revealed that FL118-ADCs exhibited a 2.6-fold increase in AUC and approximately 1.7-fold higher Cmax compared to Trodelvy®, confirming their favorable profiles and supporting their potential as a promising therapeutic approach.

Interestingly, although both 7h and SN38 exhibited similar inhibitory effects on Top1 activity, only 7h, and not SN38, could inhibit DDX5. These findings not only pave the way for deeper mechanistic explorations of FL118 and its derivatives in cancer research but also position the identified compound 7h as a promising candidate for further development.

Given that SN38 is the active metabolite of irinotecan, FL118 reduces cell viability and RAD51 in SN38-resistant LOVO cells. Our findings provide effective insights into the antitumor activity of FL118 and its potential as a therapeutic agent for overcoming irinotecan resistance in CRC.

Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML.

P1, N=84, Not yet recruiting, Roswell Park Cancer Institute | Trial completion date: May 2027 --> Oct 2027 | Initiation date: Apr 2024 --> Oct 2024 | Trial primary completion date: May 2027 --> Oct 2027