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
  • 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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