mTOR mediated anti-cancer drug discovery

doi:10.1016/j.ddstr.2009.12.001

Drug Discovery Today: Therapeutic Strategies

Volume 6, Issue 2, Summer 2009, Pages 47-55

https://doi.org/10.1016/j.ddstr.2009.12.001 Get rights and content

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and the founding member of a signaling pathway that regulates many fundamental features of cell growth and division. In cells, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Together, these complexes coordinate a variety of processes that include protein translation, autophagy, proliferation, survival and metabolism in response to nutrient, energy and growth factor signals. Consistent with its role as a growth-promoting pathway, numerous studies have found that mTOR signaling is hyper-activated in a broad spectrum of human cancers. In particular, mTORC2 is considered a primary effector of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, which is mutated in a majority of human cancers, in part through its ability to phosphorylate and regulate the proto-oncogene Akt/PKB. Many biological functions of mTOR have been pharmacologically explored using the natural product rapamycin, an allosteric inhibitor that has been reviewed extensively elsewhere. This review will focus specifically on the development of small molecule ATP-competitive inhibitors of mTOR and their prospects as a targeted therapy.

Section editor:

Robert Copeland – Epizyme Inc., Cambridge, MA 02139, USA

Section snippets

Introduction of mTOR signalling pathway

Rapamycin is a 31-membered macrocyclic lactone that was first developed as immunosuppressant by Wyeth in 1997 and more recently as an anti-cancer agent in the form of various analogs, often referred to as rapalogs. In complex with the small protein FKBP12, rapamycin binds to the FKBP12-rapamycin (FRB) domain of mTOR and inhibits its kinase activity through an allosteric mechanism that is still under investigation. Because of its exquisite selectivity, rapamycin has been an indispensable

Rapamycin and rapalogs

Rapamycin was originally identified as an antifungal compound in 1975, later discovered to have anti-tumor activity in 1984, and eventually commercialized as immunosuppressant by Wyeth in 1997. More recently, there has been a renewed interest in its anti-cancer properties, which has sparked the development of several analogs that are collectively referred to as ‘rapalogs.’ Rapamycin has very poor water solubility, severely limiting its bioavailability [18]. Thus, many of the rapalogs, such as

ATP-competitive inhibitors

The development of ATP-competitive mTOR inhibitors has historically been neglected because it was difficult to imagine an ATP-competitive inhibitor competing with the potency and selectivity of the rapalogs. Several factors converged to change this. First was the discovery of mTORC2 complex and its insensitivity to acute inhibition by rapamycin. Second was the discovery that combinations of rapamycin and ATP-competitive PI3K inhibitors or dual-mTOR/PI3K ATP-competitive compounds like PI-103

Future direction

Accumulated evidence has demonstrated that mTOR is a key node in the PI3K/Akt/mTOR signalling pathway, which is arguably the most commonly activated pathway in human cancer. As such, there is a strong rationale for targeting mTOR therapeutically, especially in cancers that are known to carry alterations in PI3K signaling. Several hereditary cancer syndromes are reasonable candidates, such as Cowden's Syndrome (PTEN), Tuberous Sclerosis Complex (TSC1 or TSC2), and Peutz-Jeghers Syndrome

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Cited by (161)

Discovery of pyrazolo[3,4-d]pyrimidines as novel mitogen-activated protein kinase kinase 3 (MKK3) inhibitors
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The dual-specificity protein kinase MKK3 has been implicated in tumor cell proliferation and survival, yet its precise role in cancer remains inconclusive. A critical step in elucidating the kinase's involvement in disease biology is the identification of potent, cell-permeable kinase inhibitors. Presently, MKK3 lacks a dedicated tool compound for these purposes, along with validated methods for the facile screening, identification, and optimization of inhibitors. In this study, we have developed a TR-FRET-based enzymatic assay for the detection of MKK3 activity in vitro and a BRET-based assay to assess ligand binding to this enzyme within intact human cells. These assays were instrumental in identifying hit compounds against MKK3 that share a common chemical scaffold, sourced from a library of bioactive kinase inhibitors. Initial hits were subsequently expanded through the synthesis of novel analogs. The resulting structure–activity relationship (SAR) was rationalized using molecular dynamics simulations against a homology model of MKK3. We expect our findings to expedite the development of novel, potent, selective, and bioactive inhibitors, thus facilitating investigations into MKK3′s role in various cancers.
MNK, mTOR or eIF4E-selecting the best anti-tumor target for blocking translation initiation
2023, European Journal of Medicinal Chemistry
Overexpression of eIF4E is common in patients with various solid tumors and hematologic cancers. As a potential anti-cancer target, eIF4E has attracted extensive attention from researchers. At the same time, mTOR kinases inhibitors and MNK kinases inhibitors, which are directly related to regulation of eIF4E, have been rapidly developed. To explore the optimal anti-cancer targets among MNK, mTOR, and eIF4E, this review provides a detailed classification and description of the anti-cancer activities of promising compounds. In addition, the structures and activities of some dual-target inhibitors are briefly described. By analyzing the different characteristics of the inhibitors, it can be concluded that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors. Simultaneous inhibition of MNK and eIF4E/eIF4G interaction may be the most promising anti-cancer method for targeting translation initiation.
Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents
2023, European Journal of Medicinal Chemistry
Citation Excerpt :
In platinum-resistant cells, in which the PKB/mTOR signalling pathway is over-regulated, this compound can re-sensitize cancer cells to the effect of carboplatin. Torkinib has also been shown to effectively enhance the response to radiotherapy and restore the sensitivity of radio-resistant cancer cells [135,148] Among the 4-aminopyrazolo[3,4-d]pyrimidine derivatives, the orally bioavailable Sapanisertib (90, INK-128, MNL0128, TAK-228) showed promising pharmacological properties towards clinical applications [149]. This compound, able to block the two complexes mTORC1 and mTORC2, entered clinical trials for the treatment of hepatocellular carcinoma, gliosarcoma, glioblastoma and other solid tumors [150,151].
The biochemical role of the PI3K/PKB/mTOR signalling pathway in cell-cycle regulation is now well known. During the onset and development of different forms of cancer it becomes overactive reducing apoptosis and allowing cell proliferation. Therefore, this pathway has become an important target for the treatment of various forms of malignant tumors, including breast cancer and follicular lymphoma. Recently, several more or less selective inhibitors targeting these proteins have been identified. In general, drugs that act on multiple targets within the entire pathway are more efficient than single targeting inhibitors. Multiple inhibitors exhibit high potency and limited drug resistance, resulting in promising anticancer agents. In this context, the present survey focuses on small molecule drugs capable of modulating the PI3K/PKB/mTOR signalling pathway, thus representing drugs or drug candidates to be used in the pharmacological treatment of different forms of cancer.
A cell-based chemical-genetic screen for amino acid stress response inhibitors reveals torins reverse stress kinase GCN2 signaling
2022, Journal of Biological Chemistry
mTORC1 and GCN2 are serine/threonine kinases that control how cells adapt to amino acid availability. mTORC1 responds to amino acids to promote translation and cell growth while GCN2 senses limiting amino acids to hinder translation via eIF2α phosphorylation. GCN2 is an appealing target for cancer therapies because malignant cells can harness the GCN2 pathway to temper the rate of translation during rapid amino acid consumption. To isolate new GCN2 inhibitors, we created cell-based, amino acid limitation reporters via genetic manipulation of Ddit3 (encoding the transcription factor CHOP). CHOP is strongly induced by limiting amino acids and in this context, GCN2-dependent. Using leucine starvation as a model for essential amino acid sensing, we unexpectedly discovered ATP-competitive PI3 kinase-related kinase inhibitors, including ATR and mTOR inhibitors like torins, completely reversed GCN2 activation in a time-dependent way. Mechanistically, via inhibiting mTORC1-dependent translation, torins increased intracellular leucine, which was sufficient to reverse GCN2 activation and the downstream integrated stress response including stress-induced transcriptional factor ATF4 expression. Strikingly, we found that general translation inhibitors mirrored the effects of torins. Therefore, we propose that mTOR kinase inhibitors concurrently inhibit different branches of amino acid sensing by a dual mechanism involving direct inhibition of mTOR and indirect suppression of GCN2 that are connected by effects on the translation machinery. Collectively, our results highlight distinct ways of regulating GCN2 activity.
Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy
2021, Bioorganic and Medicinal Chemistry Letters
The mTOR and HDAC dual suppression is meaningful for counteracting drug resistance resulted from kinase mutation and bypass mechanisms. Herein, we communicate our recent discovery of a novel structural series of mTOR/HDAC bi-functional inhibitors featuring the pyrazolopyrimidine core via pharmacophore-merging strategy. More than half of them exerted potent dual-target inhibitory activities. In particular, compound 50 exhibited IC₅₀ values of 0.49 and 0.91 nM against mTOR and HDAC1, respectively, along with remarkably enhanced anti-proliferative activity (IC₅₀ = 1.74 μM) against MV4-11 cell line than mTOR inhibitor MLN-0128 (IC₅₀ = 5.84 μM) and HDAC inhibitor SAHA (IC₅₀ = 8.44 μM). Its intracellular intervention of both mTOR signaling and HDAC was validated by the Western blot analysis. Moreover, as the first disclosed mTOR/HDAC dual inhibitor with selectivity for some specific HDAC subtypes, it has the potential to alleviate the adverse effects resulted from pan-HDAC inhibition. Attributed to its favorable in vitro performance, compound 50 is valuable for further functional investigation as a polypharmacological anti-cancer agent.
Selective AMPK activator leads to unfolded protein response downregulation and induces breast cancer cell death and autophagy
2021, Life Sciences
AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds.
A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; ¹H and ¹³C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized.
Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling.
These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.

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CancermTOR mediated anti-cancer drug discovery

Section editor:

Section snippets

Introduction of mTOR signalling pathway

Rapamycin and rapalogs

ATP-competitive inhibitors

Future direction

Cancer Cell

Trends Biochem. Sci.

Curr. Biol.

J. Biol. Chem.

Genes Dev.

Ther. Drug Monit.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Mol. Cancer Ther.

Cancer Cell

Biochim. Biophys. Acta

Nat. Chem. Biol.

Bioorg. Med. Chem. Lett.

Nat. Rev. Drug Discovery

Cancer Res.

DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival

Cell

The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1

Science

Molecular mechanisms of mTOR-mediated translational control

Nat. Rev. Mol. Cell Biol.

Targeting mTOR globally in cancer: thinking beyond rapamycin

Cell Cycle

The TOR pathway: a target for cancer therapy

Nat. Rev. Cancer.

ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy

J. Biol. Chem.

ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery

Mol. Biol. Cell.

Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy

Mol. Biol. Cell.

Growing role for the mTOR pathway

Curr. Opin. Cell. Biol.

mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1)

Biochem. J.

The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB

EMBO J.

The pharmacology of mTOR inhibition

Sci. Signal.

Cancer
mTOR mediated anti-cancer drug discovery