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  • ||||||||||  Kadcyla (ado-trastuzumab emtansine) / Roche, Enhertu (fam-trastuzumab deruxtecan-nxki) / Daiichi Sankyo, AstraZeneca, FL118 / Canget
    Development of novel topoisomerase 1 inhibitor PBX-7 payload-based ADC including tandem cleavable linker system (Section 20) -  Mar 5, 2024 - Abstract #AACR2024AACR_3591;    
    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 potent and safe ADC candidates for cancer therapy. These advancements hold great promise in addressing the current challenges in ADC development with their enhanced safety profiles and targeted efficacy.
  • ||||||||||  FL118 / Canget
    Journal:  Preparation of a camptothecin analog FLQY2 self-micelle solid dispersion with improved solubility and bioavailability. (Pubmed Central) -  Sep 7, 2022   
    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. 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.
  • ||||||||||  FL118 / Canget
    Journal:  Investigation of the Uptake and Transport of Two Novel Camptothecin Derivatives in Caco-2 Cell Monolayers. (Pubmed Central) -  Jul 1, 2022   
    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.