FL118 / Canget - LARVOL DELTA

Development of novel small-molecule DDX5 inhibitors for treating relapsed and/or refractory multiple myeloma (ASH 2025) - "Single-agent half-maximalinhibitory concentration (IC50) values were consistently in the sub-nanomolar range (as low as 0.41 nM)and showed high efficacy in combination with proteasome inhibitors/PI (e.g., Bortezomib) andImmunomodulatory drugs/IMiDs (e.g., lenalidomide). Finally, ex vivo analysis in CD138+primary bone marrow samples obtained from patients confirmed the dose-dependent depletion ofmyeloma cells following treatment with FL118 derivatives. Currently, we are evaluating the in vivo anti-tumor efficacy of FL77-32 alone or in combination with Bortezomib in transgenic mouse models ofmyeloma, including chemo-resistant cells in NSG mouse models.Our results demonstrate the potential of adding novel DDX5 inhibitors to the armamentarium of clinicaltrial-ready drug candidates for treating RRMM."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Solid Tumor • BIRC3 • BIRC5 • CDKN1A • DDX5 • KRAS • MYC • SDC1 • XIAP

Conjugating 10,11-Dimethoxy-camptothecin with an Integrin αvβ3-Targeting Peptide through a Triazine Linker for Targeted Tumor Treatment in Lung and Pancreatic Carcinoma. (PubMed, J Med Chem) - "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."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • AKT1 • BIRC5

FL496, an FL118-derived small molecule, induces growth inhibition, senescence, and apoptosis of malignant pleural mesothelioma (MPM) cells, and exhibits anti-MPM tumor efficacy strikingly superior to the pemetrexed-cisplatin combination. (PubMed, J Exp Clin Cancer Res) - "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."

IO biomarker • Journal • Genetic Disorders • Immunology • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Osteosarcoma • Pleural Mesothelioma • Primary Immunodeficiency • Sarcoma • Solid Tumor • BCL2 • BCL2L1 • BIRC5 • CASP3 • CDKN1A • DDX5 • MCL1 • TP53

REGULATION OF DDX5 BY FL118 AND ITS ASSOCIATION WITH CELLULAR SENESCENCE DURING HEPATIC STELLATE CELL ACTIVATION (AASLD 2025) - "DDX5 plays a pro-fibrotic role by promoting HSCs activation, likely through modulation of translation and cellular state. Its expression is dynamically regulated via post-translational mechanisms. Pharmacological targeting of DDX5 with FL118, which induces DDX5 degradation, may serve as a promising antifibrotic strategy by suppressing HSCs activation and global translation."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • DDX5 • TGFB1

Novel Camptothecin Derivative 9c with Enhanced Antitumor Activity via NSA2-EGFR-P53 Signaling Pathway. (PubMed, Int J Mol Sci) - "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."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • BIRC5 • KRAS • MCL1 • TP53 • XIAP

FL118 for Treating Patients With Advanced Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Roswell Park Cancer Institute | N=84 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Design, synthesis and biological evaluation of camptothecin analogue FL118 as a payload for antibody-drug conjugates in targeted cancer therapy. (PubMed, Bioorg Med Chem Lett) - "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."

Journal • Oncology • EGFR • HER-2 • TACSTD2 • TOP1

Design, synthesis and investigation of biological activity and mechanism of fluoroaryl-substituted derivatives at the FL118 position 7. (PubMed, Eur J Med Chem) - "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."

Journal • Colorectal Cancer • Oncology • Solid Tumor • DDX5 • TOP1

FL118 Enhances Therapeutic Efficacy in Colorectal Cancer by Inhibiting the Homologous Recombination Repair Pathway through Survivin-RAD51 Downregulation. (PubMed, Cancers (Basel)) - "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."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BIRC5 • HRD • RAD51

FL118: A potential bladder cancer therapeutic compound targeting H2A.X identified through library screening. (PubMed, Bioorg Chem) - "A total of 135 compounds were screened in T24 and J82 cells, revealing that FL118 significantly inhibited the proliferation of GC (gemcitabine + cisplatin)-sensitive/insensitive cells. The resistance mediated by the DNA damage repair to DNA damage caused by GC regimen can be reversed by FL118. This distinct mechanism of FL118 has the potential to complement existing mainstream treatment approaches for bladder cancer."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Development of novel topoisomerase 1 inhibitor PBX-7 payload-based ADC including tandem cleavable linker system (AACR 2024) - "Despite the remarkable success of ADCs exploiting these payloads, such as Enhertu (DS-8201a), there are still clear unmet needs, including the improvement of safety profile (minimization of ILD and neutropenia) and the development of novel ADCs with multiple MoA payloads to combat cancer heterogeneity.To address these unmet needs, we have synthesized and evaluated a series of PBX-7 payloads, derived from novel camptothecin FL118, a potent, dual inhibitor of Top 1/anti-apoptotic pathway known for its favorable safety profile...Notably, PBX-7 based ADC demonstrated remarkable efficacy in reducing tumor volume more than Enhertu in the T-DM1-resistant JIMT-1 xenograft mouse model...This linker system has a higher stability during circulation in the body and higher specific payload release in the tumor tissue than single cleavable linker.In conclusion, our research shows the promising potential of novel camptothecin PBX-7 based ADCs and tandem cleavable linker system as..."

Oncology • Solid Tumor • CTSB • HER-2

FL118 Is a Potent Therapeutic Agent against Chronic Myeloid Leukemia Resistant to BCR-ABL Inhibitors through Targeting RNA Helicase DDX5. (PubMed, Int J Mol Sci) - "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."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • BIRC5 • CASP3 • DDX5

FL118 for Treating Patients With Advanced Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=84 | Not yet recruiting | Sponsor: 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

Metastases • Trial completion date • Trial initiation date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Drug candidate granted FDA orphan drug status for pancreatic cancer (Medical Xpress) - "The U.S. Food and Drug Administration (FDA) has awarded Orphan Drug Designation to Canget BioTekpharma LLC for FL118, a drug candidate developed at Roswell Park Comprehensive Cancer Center, as a possible treatment for pancreatic cancer...FL118 has been shown in preclinical studies to eliminate both pancreatic and colorectal tumor cells by binding to DDX5, a powerful cancer-causing protein...Research recently published by Dr. Li and colleagues in the Journal of Medicinal Chemistry documents the synthesis, identification and characterization of new analogs of FL118 shown to have enhanced comparative antitumor activity."

Orphan drug • Preclinical • Pancreatic Cancer

FL118 for Treating Patients With Advanced Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=84 | Not yet recruiting | Sponsor: Roswell Park Cancer Institute

Metastases • New P1 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Structure-Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity. (PubMed, J Med Chem) - "Interestingly, RNA-Seq analyses indicated that three of the four compounds exerted antitumor effects via an MOA similar to FL118, which provided an intriguing opportunity for follow-up studies. Extended in vivo studies revealed that FL77-6 (7-(4-ethylphenyl)-FL118), FL77-9 (7-(4-methoxylphenyl)-FL118), and FL77-24 (7-(3, 5-dimethoxyphenyl)-FL118) exhibit potential for further development toward clinical trials."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Orphan Designation: Treatment of pancreatic cancer (FDA) - Date Designated: 10/23/2023

Orphan drug • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence. (PubMed, J Exp Clin Cancer Res) - "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."

Journal • Review • Genito-urinary Cancer • Infectious Disease • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • DDX5

An In Silico Study Investigating Camptothecin-Analog Interaction with Human Protein Tyrosine Phosphatase, SHP2 (PTPN11). (PubMed, Pharmaceuticals (Basel)) - "Therefore, this study aims to provide in silico rationale for the recognition and binding of FL118 and irinotecan with the catalytic domain of human protein tyrosine phosphatase-SHP2 (PTPc-SH2-SHP2, chain A). This revealed that the complex generated became stable over time. This in silico rationale identifies the novel FL118 camptothecin analog as a potent selective inhibitor of PTPc-SH2 domain of SHP2 protein, paving way for further in vitro investigations into the interactions and binding activity of analogs with SHP2 for potential therapeutic applications in PTPN11-associated disorders."

Journal • Oncology • PTPN11

Preparation of a camptothecin analog FLQY2 self-micelle solid dispersion with improved solubility and bioavailability. (PubMed, J Nanobiotechnology) - "The successful preparation, pharmacokinetics, and pharmacodynamics studies of FLQY2-SD showed that the solubility and bioavailability of FLQY2 were improved, which facilitated the further druggability development of FLQY2."

Journal • Oncology • Solid Tumor

Design, synthesis, and biological evaluation of novel 7-substituted 10,11-methylenedioxy-camptothecin derivatives against drug-resistant small-cell lung cancer in vitro and in vivo. (PubMed, Eur J Med Chem) - "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."

IO biomarker • Journal • Preclinical • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • BCL2 • BIRC5 • CASP3 • CASP9 • MCL1 • XIAP

Investigation of the Uptake and Transport of Two Novel Camptothecin Derivatives in Caco-2 Cell Monolayers. (PubMed, Molecules) - "Irinotecan and Topotecan are two Camptothecin derivatives (CPTs) whose resistance is associated with the high expression of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp)...In this study, the anti-tumor activities of FL77-28, FL77-29, and their parent, FL118 (10,11-methylenedioxy-20(S)-CPT), were evaluated and the results showed that FL77-28 and FL77-29 had stronger anti-tumor activities than FL118...The results showed that FL77-28 was not a substrate of P-gp or BCRP, but FL77-29 was mediated by P-gp. In conclusion, FL77-28 might be a promising candidate to overcome drug resistance induced by multiple efflux proteins."

Journal • Breast Cancer • Oncology • Solid Tumor

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. (PubMed, Clin Transl Med) - "DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a 'molecular glue degrader' to directly glue DDX5 and ubiquitination regulators together to degrade DDX5."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • BIRC3 • BIRC5 • DDX5 • KRAS • MCL1 • MYC • XIAP

Bone Marrow Mesenchymal Stromal Cells can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis. (PubMed, Clin Cancer Res) - "These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggests that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of anti-apoptotic proteins upregulated in MM cells through BMMSC interactions."

CAR T-Cell Therapy • Journal • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • BIRC5 • MCL1 • SDC1 • XIAP

Multiple functions of the DEAD-box RNA helicase, DDX5 (p68), make DDX5 a superior oncogenic biomarker and target for targeted cancer therapy. (PubMed, Am J Cancer Res) - "In this article, we will summarize the relevant studies on DDX5 in literature with a careful analysis and discussion of any inconsistencies encountered, and then provide our conclusions with respect to understanding the MOA of FL118, a novel small molecule. We hope that such a review will stimulate further discussion on this topic and assist in developing better strategies to treat cancer by using DDX5 as both an oncogenic biomarker and therapeutic target."

Biomarker • Journal • Review • Oncology • DDX5