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Review
. 2022 May 9:13:875372.
doi: 10.3389/fphar.2022.875372. eCollection 2022.

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Xianbo Wu  1 , Yihua Xu  2 , Qi Liang  3 , Xinwei Yang  1 , Jianli Huang  4 , Jie Wang  4 , Hong Zhang  5 , Jianyou Shi  6
Affiliations
Review

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Xianbo Wu et al. Front Pharmacol. .

Abstract

The PI3K-Akt-mTOR pathway is a viable target for cancer treatment and can be used to treat various malignant tumours, including follicular lymphoma and breast cancer. Both enzymes, PI3K and mTOR, are critical in this pathway. Hence, in recent years, an array of inhibitors targeting these two targets have been studied, showing dual PI3K/mTOR inhibition compared with single targeting small molecule inhibitors. Inhibitors not only inhibit cell proliferation but also promote cell apoptosis. These inhibitors show high potency and little drug resistance even at low doses, suggesting that PI3K/mTOR inhibitors are promising cancer drugs. Herein, we summarised the recent research of PI3K/mTOR dual inhibitors-for example, structure-activity relationship, pharmacokinetics, and clinical practice, and briefly commented on them. Clinical Trial Registration: https://clinicaltrials.gov.

Keywords: PI3K; PI3K-Akt-mTOR pathway; SAR; cancer treament; dual inhibitor; mTOR; tumour.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
PI3K-Akt-mTOR signalling pathway and relationships of several related signalling pathways.
FIGURE 2
FIGURE 2
Structures of dual PI3K/mTOR inhibitors mentioned in the article.
FIGURE 3
FIGURE 3
SAR of Quinoline core compounds.
FIGURE 4
FIGURE 4
SAR of thienopyrimidine core compounds.
FIGURE 5
FIGURE 5
SAR of triazine derivatives.
FIGURE 6
FIGURE 6
SAR of imidazonaphthyridone core compounds.
See this image and copyright information in PMC

References

    1. Al-Ghabkari A., Perinpanayagam M. A., Narendran A. (2019). Inhibition of PI3K/mTOR Pathways with GDC-0980 in Pediatric Leukemia: Impact on Abnormal FLT-3 Activity and Cooperation with Intracellular Signaling Targets. Curr. Cancer Drug Targets 19, 828–837. 10.2174/1568009619666190326120833 - DOI - PubMed
    1. Alqurashi N., Hashimi S., Alowaidi F., Ivanovski S., Wei M. (2018). Dual mTOR/PI3K Inhibitor NVP-BEZ235 A-rrests C-olorectal C-ancer C-ell G-rowth and D-isplays D-ifferential I-nhibition of 4E-BP1. Oncol. Rep. 40 (2), 1083–1092. 10.3892/or.2018.6457 - DOI - PubMed
    1. Álvarez R. M., García A. B., Riesco-Fagundo C., Martín J. I., Varela C., Rodríguez Hergueta A., et al. (2021). Omipalisib Inspired Macrocycles as Dual PI3K/mTOR Inhibitors. Eur. J. Med. Chem. 211, 113109. 10.1016/j.ejmech.2020.113109 - DOI - PubMed
    1. Andrs M., Korabecny J., Jun D., Hodny Z., Bartek J., Kuca K. (2015). Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring. J. Med. Chem. 58, 41–71. 10.1021/jm501026z - DOI - PubMed
    1. Azaro A., Massard C., Tap W. D., Cassier P. A., Merchan J., Italiano A., et al. (2021). A Phase 1b Study of the Notch Inhibitor Crenigacestat (LY3039478) in Combination with Other Anticancer Target Agents (Taladegib, LY3023414, or Abemaciclib) in Patients with Advanced or Metastatic Solid Tumors. Invest. New Drugs 39, 1089–1098. 10.1007/s10637-021-01094-6 - DOI - PubMed