FL118

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.

Together, these results indicate that FL496 is a promising anti-MPM small molecule, and its high anti-MPM potential is worthy of being further explored as a monotherapeutic agent to treat MPM patients in clinical trials.

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P1, N=0, Withdrawn, Roswell Park Cancer Institute | N=84 --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 Withdrawn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

P1, N=84, Not yet recruiting, Roswell Park Cancer Institute

We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

All the FL118 analogues showed significant cytotoxic activities in vitro with IC values in the nanomolar range and were more potent than topotecan. It is noteworthy that 9c also demonstrated potent inhibition of drug-resistant tumor growth in NCI-H446/Irinotecan and NCI-H446/EP xenograft models, the tumor growth inhibition rates were 93.42% and 84.46%, respectively. Taken together, these findings indicated that compound 9c displays outstanding antitumor activity and drug-resistance in small-cell lung cancer both in vivo and in vitro, which could be worth further research as a novel anti-tumor drug against small-cell lung cancer.