Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity

Nannan Kang
ORCID logo ,
Jun Ma
,
Yuling Hu
,
Rongrong Di
,
Lei Wang
,
Xuanling Zhang
,
Yisheng Lai
* ,
Yu Liu
*
Version 1 : Received: 21 December 2023 / Approved: 21 December 2023 / Online: 21 December 2023 (11:49:21 CET)

How to cite: Kang, N.; Ma, J.; Hu, Y.; Di, R.; Wang, L.; Zhang, X.; Lai, Y.; Liu, Y. Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity. Preprints 2023, 2023121649. https://doi.org/10.20944/preprints202312.1649.v1 Kang, N.; Ma, J.; Hu, Y.; Di, R.; Wang, L.; Zhang, X.; Lai, Y.; Liu, Y. Targeting MutT homolog 1 (MTH1) for breast cancer suppression by a novel MTH1 inhibitor MA-24 with tumor-selective toxicity. Preprints 2023, 2023121649. https://doi.org/10.20944/preprints202312.1649.v1

Abstract

Background: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells are addicted to MTH1 for sur-vival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. Methods: MA-24 was screened by malachite green colorimetric assay from MTH1 inhibitors and the kinetic characteristics of MA-24 was assessed. Binding features of MA-24 with MTH1 was as-certained through molecular docking, and cytotoxic activity of MA-24 was validated in vitro and in vivo. Target engagement assays, comet assay and western blot confirmed that the intracellular target and mechanism of MA-24. Results: MA-24 with potent antitumor bioactivity both in vitro and in vivo. MA-24 competitively inhibited the MTH1 and further induce DNA strand breaks, leading to increased apoptosis of cancer cells depending on upregulation of cleaved-caspase 3 – cleaved-PARP axis. Especially, MA-24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). Conclusions: MA-24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great po-tential for further development MA-24 as an anti-cancer drug.

Keywords

Breast cancer, MutT homolog 1(MTH1), Antitumor activity, Oxidized nucleotide, MA-24

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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