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. 2022 Feb 8;5(3):149-155.
doi: 10.1021/acsptsci.1c00230. eCollection 2022 Mar 11.

Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy

Tianyi Wang  1   2   3 , Kaiqi Long  1   2   3 , Yang Zhou  1   2   3 , Xiaoding Jiang  4 , Jinzhao Liu  3 , John H C Fong  5 , Alan S L Wong  5   6 , Wai-Lung Ng  4 , Weiping Wang  1   2   3
Affiliations

Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy

Tianyi Wang et al. ACS Pharmacol Transl Sci. .

Erratum in

Abstract

As an important regulator of cell metabolism, proliferation, and survival, mTOR (mammalian target of rapamycin) signaling provides both a potential target for cancer treatment and a research tool for investigation of cell metabolism. One inhibitor for both mTORC1 and mTORC2 pathways, OSI-027, exhibited robust anticancer efficacy but induced side effects. Herein, we designed a photoactivatable OSI-027 prodrug, which allowed the release of OSI-027 after light irradiation to inhibit the mTOR signaling pathway, triggering autophagy and leading to cell death. This photoactivatable prodrug can provide novel strategies for mTOR-targeting cancer therapy and act as a new tool for investigating mTOR signaling and its related biological processes.

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Conflict of interest statement

The authors declare the following competing financial interest(s): A US provisional patent application was filed with No. 63/215,814.

Figures

Figure 1
Figure 1
Schematic illustration of the optochemically controlled strategy. Caged mTOR inhibitor, cOSI-027, cannot bind to mTOR protein efficiently. Light irradiation at 420 nm releases OSI-027, which can bind to the ATP-binding site of mTOR and inhibit both mTORC1 and mTORC2 signaling.
Figure 2
Figure 2
Chemical structure and molecular docking analysis of OSI-027 (a) and cOSI-027 (b). The hydrogen bonding interactions are indicated by green dash lines.
Figure 3
Figure 3
Optochemical properties of OSI-027, cOSI-27, and DEACM. (a) UV–vis spectra of OSI-027, cOSI-027, and DEACM. (b) UV–vis absorption spectra of cOSI-027 after light irradiation. (c) Fluorescence spectra of cOSI-027 after light irradiation. The excitation wavelength is 380 nm. (d) HPLC analysis of cOSI-027 after light irradiation, showing a clear photochemical conversion to desired products. The indicated drugs were dissolved in H2O at a concentration of 50 μM for (a–c). Also, the drugs were dissolved in aqueous solution of acetonitrile and water (1:1, v/v) at a concentration of 100 μM for (d). Light irradiation: 420 nm and 70 mW/cm2.
Figure 4
Figure 4
(a) Representative Western blot result of mTOR signaling and the autophagy level in A549 cells at 24 h after treatment with the indicated drugs (50 μM) and light irradiation (420 nm, 70 mW/cm2, and 3 min) (n = 3). (b) Fluorescence analysis of mCherry-GFP-LC3-transduced HeLa cells at 24 h after treatment with the indicated drugs (50 μM) and light irradiation (420 nm, 70 mW/cm2, and 3 min) (n = 3). (c) Quantification of the number of LC3 puncta per cell for cells treated in (b) (at least 100 cells per group were analyzed for the quantification).
Figure 5
Figure 5
Cell viability analysis of A549 cells at 48 h after treatment with the indicated drugs and light irradiation (420 nm, 70 mW/cm2, and 3 min).
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