2. Academic Validation
  3. Structure-Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity

Structure-Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity

  • J Med Chem. 2023 Dec 28;66(24):16888-16916. doi: 10.1021/acs.jmedchem.3c01589.
Wenchao Wang 1,  Xiang Ling 1 2,  Ruojiong Wang 1,  Haonan Xiong 1,  Liuzhi Hu 1,  Zhikun Yang 1,  Hong Wang 1,  Yali Zhang 3,  Wenjie Wu 4 2,  Prashant K Singh 5,  Jianmin Wang 3,  Fengzhi Li 4 6,  QingYong Li 1
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals & Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2 Canget BioTekpharma, LLC, Buffalo, New York 14203, United States.
  • 3 Department of Bioinformatics & Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, United States.
  • 4 Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, United States.
  • 5 Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, United States.
  • 6 Developmental Therapeutics (DT) Program, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, United States.
PMID: 38100041 DOI: 10.1021/acs.jmedchem.3c01589
Abstract

Structurally, FL118 is a camptothecin analogue and possesses exceptional antitumor efficacy against human Cancer through a novel mechanism of action (MOA). In this report, we have synthesized and characterized 24 FL118 Position 7-substituted and 24 FL118 Position 9-substituted derivatives. The top compounds were further characterized for their MOA in colorectal Cancer (CRC) models using CRC patient-derived xenograft (PDX) models and pancreatic Cancer PDX models to evaluate their antitumor activities. Four FL118 Position 7-substituted derivatives showed significantly better antitumor efficacy than the FL118 Position 9-substituted derivatives. The four identified compounds also appeared to have better antitumor activity than their parental platform FL118. 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.

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