FL118 / Canget - LARVOL DELTA

FL118 Granted FDA Rare Pediatric Disease Designation and Orphan Drug Designation for Osteosarcoma (Roswell Park Comprehensive Cancer Center)

FDA event • Orphan drug • Osteosarcoma

DDX5 (p68) and UbE2T as emerging superior cancer therapeutic targets: dual molecular glue target degradation by FL118 for conquering difficult-to-treat cancers. (PubMed, J Exp Clin Cancer Res) - "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),..."

Journal • Review • Brain Cancer • Castration-Resistant Prostate Cancer • Colorectal Cancer • Ewing Sarcoma • Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Glioblastoma • Glioma • Oncology • Osteosarcoma • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Cancer • Sarcoma • Solid Tumor • Targeted Protein Degradation • ABCB1 • ABCC1 • ABCG2 • DDX5 • NANOG • UBE2T

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..."

ADC • Oncology • Solid Tumor • CTSB • HER-2

DDX5: A Versatile RNA Helicase in Cancer and Cell Fate Determination-Linking c-Myc and JAK2 V617F Signaling to Emerging Therapeutics. (PubMed, J Biochem) - "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."

JAK2V617F • Journal • Myeloproliferative Neoplasm • Oncology • DDX5 • JAK2 • MYC

EBV nuclear antigen 1 hijacks DDX5/BZLF1 axis to facilitate viral lytic replication. (PubMed, Virol Sin) - "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."

Journal • Epstein-Barr Virus Infections • Gastric Cancer • Infectious Disease • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • Targeted Protein Degradation • DDX5

Targeting DDX5 using FL118 suppresses mTOR signaling and tumorigenicity in JAK2V617F-driven myeloproliferative neoplasms. (PubMed, Int Immunopharmacol) - "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."

JAK2V617F • Journal • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Transplantation • DDX5 • JAK2 • STAT5

Discovery and Preclinical Evaluation of PBX-7016, a Methylenedioxy-Camptothecin Payload for Antibody-Drug Conjugates with Enhanced Therapeutic Potential. (PubMed, J Med Chem) - "Hybrid molecules combining FL118 and Exatecan pharmacophores were synthesized and tested in vitro, yielding three lead compounds characterized by dual Topo1 inhibition and antiapoptotic protein suppression...When benchmarked against Enhertu, these ADCs showed superior bystander killing and in vivo efficacy across multiple xenograft models...Notably, in vitro ADME profiling and rodent toxicology studies confirmed a favorable safety profile and good tolerability. PBX-7016 represents a differentiated camptothecin payload with strong translational promise, and its ADCs are currently advancing through Phase I trials."

Journal • Preclinical • Oncology

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

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