This phase I trial tests the safety, side effects, and best dose of FL118 in treating patients with pancreatic ductal adenocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). FL118 is a small anti-tumor molecule that inhibits the expression of multiple cancer-associated anti-apoptotic proteins. An anti-apoptotic protein is a protein that interferes with or inhibits cell death. In adults, apoptosis is used to rid the body of cells that have been damaged beyond repair. Apoptosis also plays a role in preventing cancer. If apoptosis is for some reason prevented, it can lead to uncontrolled cell production that can subsequently develop into a tumor. FL118 has been shown to inhibit or block the proteins that prevent damaged/mutated (genetically changed) cells from dying, and, by doing so, prevent the growth of cancerous cells and tumor development.

Start Date01 Oct 2025

Sponsor / Collaborator

Roswell Park Comprehensive Cancer Center

100 Clinical Results associated with FL-118

100 Translational Medicine associated with FL-118

100 Patents (Medical) associated with FL-118

141

Literatures (Medical) associated with FL-118

01 Apr 2025·Bioorganic & Medicinal Chemistry Letters

Design, synthesis and biological evaluation of camptothecin analogue FL118 as a payload for antibody-drug conjugates in targeted cancer therapy

Article

Author: Shin, Seunggun ; Chun, Younghwa ; Jung, Jin Kyo ; Jung, Doo Young ; Lee, Byeong Sung ; Lee, Jin Soo ; Cho, Hyun Yong ; Kweon, Sohui ; Go, Areum ; Mathi, Gangadhar Rao

FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC₅₀ values as low as 0.025 nM in Trop2-positive FaDu cells. 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 C_max compared to Trodelvy®, confirming their favorable profiles and supporting their potential as a promising therapeutic approach.

01 Feb 2025·European Journal of Medicinal Chemistry

Design, synthesis and investigation of biological activity and mechanism of fluoroaryl-substituted derivatives at the FL118 position 7

Article

Author: Li, Lei ; An, Lianhao ; Li, Dan ; Ling, Xiang ; Li, Fengzhi ; Fountzilas, Christos ; Wang, Hong ; Wang, Ruojiong ; Xiong, Haonan ; Li, Qingyong ; Wang, Mengke ; Yang, Zhikun ; Lei, Junrong ; Wang, Wenchao ; Dong, Fangze

Addition of fluorine atoms into chemical compounds is a validated strategy to enhance their physical, chemical and biological properties. In this study, FL118, a novel camptothecin-related small molecule known for its unique mechanism of action and superior antitumor efficacy, was utilized as a foundational drug platform. By replacing the hydrogen atom at position 7 of FL118 with a fluoroaryl group, a diverse array of FL118 derivatives were synthesized. Our investigations revealed that the majority of these newly synthesized compounds exhibited improved cytotoxicity compared to FL118, with some demonstrating enhanced in vivo antitumor efficacy. Among these derivatives, compound 7h stood out and was subjected to detailed analysis. Compound 7h demonstrated a remarkable ability to inhibit colorectal cancer (CRC) cell colony formation and cell migration, while also promoting reactive oxygen species (ROS) production and CRC cell apoptosis. Notably, our studies unveiled that the presence of DDX5 could modulate Topoisomerase I (Top1) activity, a process effectively reversed by a low concentration of 7h, but not SN38. Moreover, only 7h was able to decrease DDX5 expression, SN38 was not. Molecular docking studies further supported the binding of 7h to DDX5. 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.

01 Dec 2024·Bioorganic Chemistry

FL118: A potential bladder cancer therapeutic compound targeting H2A.X identified through library screening

Article

Author: Gong, Yuwen ; Yang, Engaung ; Wang, Juan ; Shi, Yibo ; Ji, Luhua ; Cui, Shu ; Luo, Xiongfei ; Ding, Hui ; Chen, Chaohu ; Zhang, Zhijun ; Wang, Zhiping ; Liu, Yingqian ; Wang, Yingru ; Fan, Guangrui

The treatment of bladder cancer is limited by low drug efficacy and drug resistance. Hence, this study aimed to screen and identify potential drug precursors and investigate their mechanism of action. A set of camptothecin derivatives showing high anti-tumor potential was selected from early-stage research or literature and synthesized to construct a compound library. 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. FL118 exhibited excellent penetration and killing ability in organoids and three GC-insensitive patient-derived xenografts. Chemical proteomic and docking calculations were employed to identify binding proteins, indicating that FL118 can bind into H2A.X and its entwined DNA. The results of Cellular thermal shift assay and surface plasmon resonance (K_d = 3.77E-6) support the above findings. Fluorescence localization revealed widespread binding of FL118 within the cell nucleus. Furthermore, WB showed that FL118 increased cellular DNA damage, resulting in significant cell cycle inhibition. The binding of FL118 to H2A.X hindered the damage repair process, leading to apoptosis. Controllable adverse reactions were observed in mice treated with FL118. In conclusion, FL118 may be a superior anti-bladder cancer compound that acts as a molecular glue binding to both H2A.X and DNA. 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.

100 Deals associated with FL-118

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Pancreatic Ductal Adenocarcinoma	Preclinical	US	Roswell Park Comprehensive Cancer Center	01 Oct 2025
Metastatic Pancreatic Ductal Adenocarcinoma	Preclinical	US	Roswell Park Comprehensive Cancer Center	01 Oct 2025
Colorectal Cancer	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Head and Neck Neoplasms	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Mesothelioma	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Osteosarcoma	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Ovarian Cancer	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Pancreatic Cancer	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Prostatic Cancer	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023
Soft Tissue Sarcoma	Preclinical	US	Canget BioTekpharma LLC	12 Oct 2023

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