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Am J Cancer Res. 2017 Dec 1;7(12):2350-2394. eCollection 2017.

Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?

Author information

1
Department of Pharmacology & Therapeutics, Roswell Park Cancer InstituteBuffalo, New York, USA.
2
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, School of Medicine and Pharmacy, Ocean University of ChinaQingdao, China.
3
Collaborative Innovation Center of Yangtze River Region Green Pharmaceuticals, Zhejiang University of TechnologyHangzhou, China.
4
Canget BioTekpharmaBuffalo, New York, USA.

Abstract

Camptothecin (CPT) was discovered from plant extracts more than 60 years ago. Since then, only two CPT analogues (irinotecan and topotecan) have been approved for cancer treatment, although several thousand CPT derivatives have been synthesized and many of them were actively studied in our research community over the past 6+ decades. In this review article, we briefly summarize: (1) the discovery and early development of CPTs, (2) the recognized CPT mechanism of action (MOA), (3) the synthesis of CPT and CPT analogues, and (4) the structure-activity relationship (SAR) of CPT and its analogues. Next, we provide evidence that certain CPT analogues can exert improved efficacy with low toxicity independently of topoisomerase I (Top1) inhibition; instead, these CPT analogues use novel MOAs by targeting important cancer survival-associated oncogenic proteins and/or by bypassing various treatment-resistant mechanisms. We then present a comprehensive review of the most advanced CPT analogues in clinical development, with the goal of resolving why no new CPTs have been FDA approved for cancer treatment, beyond irinotecan and topotecan. We argue that new CPT Top1 inhibitor drugs are unlikely being found to be significantly better than irinotecan and/or topotecan in terms of the overall antitumor activity and toxicity. The significance of CPT analogues that possess novel MOAs has not been sufficiently recognized so far. In our opinion, this is a research area with great potential to make a breakthrough for development of the next generation of CPT analogues that possess high efficacy (due to novel targets) and low toxicity (due to low inhibition of Top1 activity/function) for effective treatment of human disease, including cancer.

KEYWORDS:

Camptothecin (CPT); FL118; Mcl-1; XIAP; analogue/derivative; cIAP2; clinical trials; novel mechanism of action; survivin; topoisomerase I (Top1)

PMID:
29312794
PMCID:
PMC5752681

Conflict of interest statement

FL118 and FL118 core structure-based analogues are currently under further development in Canget BioTekpharma (www.canget-biotek.com), a Roswell Park Cancer Institute-spinoff company. FL, TJ and XL are initial investors in Canget for development of FL118 and FL118 core structure-relevant anticancer agents.

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