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Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1

Acta Pharmacologica Sinica volume 45, pages 1044–1059 (2024)Cite this article

Abstract

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2–4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1–6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

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Fig. 1: Chemical structures of representative targeted small-molecule agents for the treatment of mCRC, along with their respective target(s) given in brackets below.
Fig. 2
Scheme 1
Fig. 3: Biological evaluation of compound 4 in vitro.
Fig. 4: The effect of compound 4 on cell cycle arrest, apoptosis, and cellular senescence.
Fig. 5: Inhibitory effect of compound 4 on patient-derived CRC organoids.
Fig. 6: In vivo efficacy of compound 4 in a PDX xenograft model of CRC (n = 5 per group).
Fig. 7: Identification of AKT1 as the direct binding target of compound 4.
Fig. 8: Compound 4 inhibits CRC by targeting AKT1.

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Acknowledgements

This work was generously supported by the National Natural Science Foundation of China (NNSFC) (No. 21772101) to WCZ, the National Natural Science Foundation of China (NNSFC) (Nos. 81973356 and 82373906) to CLS, and the Fundamental Research Funds for the Central Universities in Nankai University (Nos. 63231108, ZB22010404, and 63221331) to CLS.

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  1. These authors contributed equally: Han Zhang, Fei Xie, Xiao-ya Yuan, Xin-tong Dai

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  1. The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China

    Han Zhang, Fei Xie, Xiao-ya Yuan, Xin-tong Dai, Yun-feng Tian, Ming-ming Sun, Si-qi Yu, Jia-you Cai, Bin Sun, Wei-cheng Zhang & Chang-liang Shan

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Contributions

WCZ and CLS designed the study. HZ, FX, XYY, YFT, XTD, MMS, SQY, JYC and BS performed the experiments. WCZ and CLS wrote the manuscript. HZ, FX, WCZ and CLS revised the manuscript. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Wei-cheng Zhang or Chang-liang Shan.

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This study was carried out in accordance with the recommendations of Requirements of the Ethical Review System of Biomedical Research Involving Human by National Health and Family Planning Commission of China, Nankai University Laboratory Animal Welfare Ethics Review Committee (Approval No. 2023-SYDWLL-000066), Biomedical Ethics Committee of Nankai University (Ethics Document No. NKUIRB2023024), and Tianjin Central Hospital of Gynecology Obstetrics with written informed consent from all subjects. All subjects have been given a written informed consent in accordance with the Declaration of Helsinki.

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Zhang, H., Xie, F., Yuan, Xy. et al. Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1. Acta Pharmacol Sin 45, 1044–1059 (2024). https://doi.org/10.1038/s41401-024-01231-w

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