First-generation mTOR Inhibitors Research Articles

MTOR hyperactivity and RICTOR amplification as targets for personalized treatments in malignancies.

The increasing knowledge of molecular alterations in malignancies, including mutations and regulatory failures in the mTOR (mechanistic target of rapamycin) signaling pathway, highlights the importance of mTOR hyperactivity as a validated target in common and rare malignancies. This review summarises recent findings on the characterization and prognostic role of mTOR kinase complexes (mTORC1 and mTORC2) activity regarding differences in their function, structure, regulatory mechanisms, and inhibitor sensitivity. We have recently identified new tumor types with RICTOR (rapamycin-insensitive companion of mTOR) amplification and associated mTORC2 hyperactivity as useful potential targets for developing targeted therapies in lung cancer and other newly described malignancies. The activity of mTOR complexes is recommended to be assessed and considered in cancers before mTOR inhibitor therapy, as current first-generation mTOR inhibitors (rapamycin and analogs) can be ineffective in the presence of mTORC2 hyperactivity. We have introduced and proposed a marker panel to determine tissue characteristics of mTOR activity in biopsy specimens, patient materials, and cell lines. Ongoing phase trials of new inhibitors and combination therapies are promising in advanced-stage patients selected by genetic alterations, molecular markers, and/or protein expression changes in the mTOR signaling pathway. Hopefully, the summarized results, our findings, and the suggested characterization of mTOR activity will support therapeutic decisions.

Molecular recognition of some novel mTOR kinase inhibitors to develop anticancer leads by drug-likeness, molecular docking and molecular dynamics based virtual screening strategy

Cancer is the second leading cause of death worldwide. Among various anticancer drug targets, mTOR is noteworthy. Numerous first-generation mTOR inhibitors are already approved and few second-generation mTOR inhibitors targeting the kinase domain are in the clinical trials, but yet to reach the market, and many lead to serious toxicities. Here we are focused to discover some novel kinase inhibitors from the ZINC database which may effectively inhibit mTOR kinase. For this, computational chemistry and pharmacophore-based ZINC database search has been adopted. Series of virtual screening analysis lead to the discovery of 5 active hits. Among these 5, compound 4 (ZINC79476038) having binding energy of −8.9 Kcal/mol shows maximum interactions within the binding pocket. Study proved that all these compounds can potentially inhibit mTOR kinase and can be successfully developed as anticancer agents. We further proved that these compounds are not only active for general cancers like lung, breast, colon, and other peripheral cancers but also equally active in CNS, targeting numerous brain cancers.

The Bumpy Road towards mTOR Inhibition in Glioblastoma: Quo Vadis?

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is a lethal brain tumor with a poor prognosis. Despite recent advances in the molecular biology of GBM, neuro-oncologists have very limited treatment options available to improve the survival of GBM patients. A prominent signaling pathway implicated in GBM pathogenesis is that of the mechanistic target of rapamycin (mTOR). Attempts to target the mTOR pathway with first-generation mTOR inhibitors appeared promising in the preclinical stage; however, results have been disappointing in clinical trials, owing to the heterogeneous nature of GBM, escape mechanisms against treatment, the blood–brain barrier, drug-related toxicities, and the imperfect design of clinical trials, among others. The development of next-generation mTOR inhibitors and their current evaluation in clinical trials have sparked new hope to realize the clinical potential of mTOR inhibitors in GBM. Meanwhile, studies are continuously furthering our understanding of mTOR signaling dysregulation, its downstream effects, and interplay with other signaling pathways in GBM tumors. Therefore, it remains to be seen whether targeting mTOR in GBM will eventually prove to be fruitful or futile.

Playing the Devil's Advocate: Should We Give a Second Chance to mTOR Inhibition in Renal Clear Cell Carcinoma? - ie Strategies to Revert Resistance to mTOR Inhibitors.

In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician’s expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of this class of drugs. Moreover, we describe some of the possible strategies to overcome the mechanisms of resistance and their clinical experimentation, with particular focus on novel mTOR inhibitors and the combinations of mTOR inhibitors and other anti-cancer drugs.

Chemical and Structural Strategies to Selectively Target mTOR Kinase.

Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First‐generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP‐competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP‐competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3‐kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds’ ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.

Role of the Mammalian Target of Rapamycin Pathway in Liver Cancer: From Molecular Genetics to Targeted Therapies.

Primary liver cancers, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), are highly lethal tumors, with high worldwide frequency and few effective treatment options. The mammalian target of rapamycin (mTOR) complex is a central regulator of cell growth and metabolism that integrates inputs from amino acids, nutrients, and extracellular signals. The mTOR protein is incorporated into two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Specifically, mTORC1 regulates protein synthesis, glucose and lipid metabolism, and autophagy, whereas mTORC2 promotes liver tumorigenesis through modulating the adenine/cytosine/guanine family of serine/threonine kinases, especially the protein kinase B proteins. In human HCC and iCCA samples, genomics analyses have revealed the frequent deregulation of the mTOR complexes. Both in vitro and in vivo studies have demonstrated the key role of mTORC1 and mTORC2 in liver-tumor development and progression. The first-generation mTOR inhibitors have been evaluated for effectiveness in liver-tumor treatment and have provided unsatisfactory results. Current research efforts are devoted to generating more efficacious mTOR inhibitors and identifying biomarkers for patient selection as well as for combination therapies. Here, we provide a comprehensive review of the mechanisms leading to a deregulated mTOR signaling cascade in liver cancers, the mechanisms whereby the mTOR pathway contributes to HCC and iCCA molecular pathogenesis, the therapeutic strategies, and the challenges to effectively inhibit mTOR in liver-cancer treatment. Conclusion: Deregulated mTOR signaling significantly contributes to HCC and iCCA molecular pathogenesis. mTOR inhibitors, presumably administered in association with other drugs, might be effective against subsets of human liver tumors.

Targeting mTOR for fighting diseases: A revisited review of mTOR inhibitors

mTOR (mammalian target of rapamycin), which is a serine/threonine kinase, has been well-established as being closely correlated with the occurrence of various human diseases, such as tumors and neurodegenerative diseases. Inhibition of the mTOR signaling pathways may effectively block the abnormal signal transduction of various growth factors and thereby block the occurrence and development of diseases. Of note, first-generation mTOR inhibitors are mainly reported to be rapamycin and its derivatives and second-generation mTOR inhibitors that consist of several ATP-competitive kinase inhibitors. Interestingly, the third-generation mTOR inhibitor, RapaLink-1, mediates rapamycin and mTOR kinase inhibitors via the same molecule and shows much higher efficiency. In addition, there are many mTOR inhibitors that have potential therapeutic effects for tumors and other types of diseases. Thus, we focus on summarizing the basic structures of mTOR and its complexes, some key upstream and downstream signaling pathways, and the structures and characteristics of the three generations of mTOR inhibitors in disease. Together, these findings may provide a better understanding of mTOR-regulated mechanisms and their inhibitors for fighting human diseases in the near future.

Pharmacophore-guided fragment-based design of novel mammalian target of rapamycin inhibitors: extra precision docking, fingerprint-based 2D and atom-based 3D-QSAR modelling

Rapamycin and their derivatives known as rapalogs were the first-generation mTOR inhibitors which interacted with mTORC1 but not with the mTORC2 protein. Second-generation inhibitors could bind with both and showed excellent anti-proliferative activity. Our aim was to design novel mTOR inhibitors which could bind at both the allosteric and the kinase site. The FRB domain is present in both the mTORC1 and mTORC2 protein complexes. We have employed e-pharmacophore-guided fragment-based design to develop novel mTOR inhibitors. The affinity of designed molecules at both the sites was analysed using molecular docking in extra precision mode. The atom-based 3D-QSAR model was developed to predict the activity while the fingerprint-based 2D-QSAR model was employed to refine an identified hit as potent dual mTOR inhibitor. Ligand ASK23 showed a docking score of −15.452 kcal/mol at the allosteric site (PDB ID 5GPG) while ASK38 showed a docking score of −11.535 kcal/mol at the kinase site (PDB ID 4JT6). Ligand ASK12 showed binding energy of −106.23 kcal/mol at the allosteric site. Refined molecule ASK12a from ASK12 showed the highest predicted activity (pIC50: 6.512). The stability of the best hits and receptor complex was analysed using molecular dynamics simulation studies. Herein we report five potential mTOR dual inhibitors based on the predicted activity, drug-likeness analysis and off-target effects. To the best of our knowledge, this is the first report on pharmacophore-guided fragment-based drug design for mTOR inhibitors. This design strategy can be used for the rational drug design against other proteins for which only apo-structures are available. Communicated by Ramaswamy H. Sarma

Abstract IA25: Third-generation inhibitors of mTOR

Abstract Precision medicines exert selective pressure on tumor cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA–AKT–mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in “N-of-1” cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we seek to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumors with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants. Citation Format: Kevan M. Shokat. Third-generation inhibitors of mTOR. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA25.

Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes.

Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR) inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus). This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus) are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease). Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is impossible to select patients not benefiting from addition of everolimus to exemestane. Side effects and impact on quality of life are other important issues discussed in this review. Second-generation mTOR inhibitors and dual mTOR-phosphatidylinositol-3-kinase inhibitors are currently being evaluated in clinical trials.

MTOR signaling and drug development in cancer

Mammalian target of rapamycin (mTOR) is a protein kinase of the PI3K/Akt signaling pathway. Activation of mTOR in response to growth, nutrient and energy signals leads to an increase in protein synthesis, which is required for tumor development. This feature makes mTOR an attractive target for cancer therapy. First-generation mTOR inhibitors are sirolimus derivatives (rapalogs), which have been evaluated extensively in cancer patients. Everolimus and temsirolimus are already approved for the treatment of renal-cell carcinoma. Temsirolimus is also approved for the treatment of mantle-cell lymphoma. These drugs, in addition to ridaforolimus (formerly deforolimus) and sirolimus, are currently being evaluated in clinical trials of various cancers. Second-generation mTOR inhibitors are small molecules that target the kinase domain, and have also entered clinical development. Clinical trials are underway to identify additional malignancies that respond to mTOR inhibitors, either alone or in combination with other therapies. Future research should evaluate the optimal drug regimens, schedules, patient populations, and combination strategies for this novel class of agents.

Getting more out of mTOR

UCSF researchers have designed mTOR inhibitors that may have improved anticancer activity compared with rapamycin and other first-generation mTOR inhibitors. The compounds have been licensed by Intellikine Inc.