(5-(2-4-bis((3s)-3-methylmorpholin-4-yl)pyrido(2-3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol and Neoplasms

Phosphatidylinositol-3 kinase-related kinases (PIKKs) belong to a family of atypical serine/threonine kinases in humans. They actively participate in a diverse set of cellular functions such as meiotic, V(D)J recombination, chromosome maintenance, DNA damage sensing and repair, cell cycle progression and arrest. ATR, ATM, DNA-PKcs, mTOR and hSMG are the members of the PIKK family that play an important role in in cancer cell proliferation, autophagy, and cell survival to radio and chemotherapy. Thereby targeting these PIKK kinases in cancer along with chemo/radiotherapy agents, can help in differential cytotoxicity towards cancer cell over the normal cell. In this review, we compile the various small molecule kinase inhibitors with respect to structural and strategic targeting of PIKK family members. Rapalogs, AZD8055, AZD2014, OSI-027, INK-128, MLN0128, VX970, NVP-BEZ235, Torin2, AZ20, and AZ31 are the diverse scaffolds which have successfully made into the pre-clinical trials either as mono or combinatorial therapy for the treatment of various human cancers. Their synthesis and pre-clinical trial highlight the challenges associated in the development process.

Topics: Benzamides; Benzoxazoles; Humans; Imidazoles; Molecular Targeted Therapy; Morpholines; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrimidines; Signal Transduction; Triazines

AZD8055 is a small-molecule inhibitor of mTOR (mammalian target of rapamycin) kinase activity. The present review highlights molecular and phenotypic differences between AZD8055 and allosteric inhibitors of mTOR such as rapamycin. Biomarkers, some of which are applicable to clinical studies, as well as biological effects such as autophagy, growth inhibition and cell death are compared between AZD8055 and rapamycin. Potential ways to develop rational combinations with mTOR kinase inhibitors are also discussed. Overall, AZD8055 may provide a better therapeutic strategy than rapamycin and analogues.

Topics: Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Humans; Medical Oncology; Molecular Targeted Therapy; Morpholines; Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Over the past few years a number of components of the PI3K/mTOR pathway have been the subject of intense drug discovery activities both in pharmaceutical companies and in academia. This review article summarizes progress made in the identification and development of allosteric and ATP-competitive kinase inhibitors of mTOR and their potential therapeutic use in oncology.

Topics: Adenosine Triphosphate; Allosteric Regulation; Antineoplastic Agents; Humans; Neoplasms; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; TOR Serine-Threonine Kinases

This is the first phase I, dose-finding study of AZD8055, a first-in-class dual mTORC1/2 inhibitor, in Japanese patients with advanced solid tumors.. Patients received a single oral dose of AZD8055, followed by twice-daily (BID) dosing. The starting dose was 10 mg with dose escalations in subsequent cohorts to a maximum of 90 mg BID or a non-tolerated dose.. Seventeen patients were dosed: 10 mg (n=3), 40 mg (n=4), 60 mg (n=3), 90 mg (n=7). In the 90 mg cohort, one dose limiting toxicity (n=1) of increased aspartate aminotransferase and increased alanine aminotransferase was observed in the 90 mg BID cohort (n=1). Four patients, all in the 90 mg BID cohort, experienced a serious adverse event considered to be related to AZD8055: increased alanine aminotransferase (n=3), increased aspartate aminotransferase (n=3), increased gamma-glutamyltransferase (n=2). The 90 mg BID dose was considered as tolerated in Japanese patients but higher doses were not investigated as this dose was also the maximum tolerated dose in Western patients. AZD8055 was rapidly absorbed with greater-than-proportional increases in exposure with increasing dose. No responses were reported, but two patients had stable disease. Mean pAKT and p4EBP1 levels decreased in most cohorts. Conclusion The tolerability and pharmacokinetic profiles of AZD8055 in Japanese patients were similar to those reported in Western patients.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Middle Aged; Morpholines; Multiprotein Complexes; Neoplasms; Protein Kinase Inhibitors; Radiography; TOR Serine-Threonine Kinases; Treatment Outcome

This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055.. Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID).. Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t(max) ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ≥ 4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ≥ 40 mg BID (n=8 at day 35).. The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen.

Topics: Adult; Aged; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Lymphoma; Male; Maximum Tolerated Dose; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Middle Aged; Morpholines; Multiprotein Complexes; Neoplasms; TOR Serine-Threonine Kinases

A number of mammalian target of rapamycin (mTOR) inhibitors have been approved for the treatment of certain types of cancer or are currently undergoing clinical trials. However, mTOR targeted therapy exerts selective pressure on tumour cells, which leads to the preferential growth of resistant subpopulations. There are two classes of mTOR inhibitors: i) The rapalogs, such as rapamycin, which bind to the 12‑kDa FK506‑binding protein/rapamycin‑binding domain of mTOR; and ii) the ATP‑competitive inhibitors, such as AZD8055, which block the mTOR kinase domain. Cardamonin inhibits mTOR by decreasing the expression of regulatory‑associated protein of mTOR (Raptor), a mechanism of action which differs from the currently available mTOR inhibitors. The present study investigated the inhibitory effects of cardamonin on mTOR inhibitor‑resistant cancer cells. HeLa cervical cancer cells and MCF‑7 breast cancer cells were exposed to high concentrations of mTOR inhibitors, until resistant clones emerged. Cytotoxicity was measured using the MTT and colony forming assays. The inhibitory effect of cardamonin on mTOR signalling was assessed by western blotting. The resistant cells were less sensitive to mTOR inhibitors compared with the parental cells. Consistent with the anti‑proliferation effect, rapamycin and AZD8055 had no effect on the phosphorylation of rapamycin‑sensitive sites on ribosomal protein S6 kinase B1 (S6K1) and AZD8055‑sensitive sites on protein kinase B and eukaryotic translation initiation factor 4E binding protein 1 (Thr 37/46), respectively, in rapamycin‑ and AZD8055‑resistant cells. Cardamonin inhibited cell proliferation and decreased the phosphorylation of mTOR and S6K1, as well as the protein level of raptor, in the mTOR inhibitor‑resistant cells. Therefore, cardamonin may serve as a therapeutic agent for patients with cervical and breast cancer resistant to mTOR inhibitors.

Topics: Cell Proliferation; Chalcones; Drug Resistance, Neoplasm; HeLa Cells; Humans; MCF-7 Cells; Morpholines; Neoplasm Proteins; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

The involvement of mammalian target of rapamycin (mTOR) in the positive regulation of oncogenesis has been well documented and thus mTOR has emerged as an attractive cancer therapeutic target. Although rapamycin and its analogues (rapalogs) are FDA-approved for the treatment of certain cancers, major success in targeting mTOR, particularly with new generation mTOR kinase inhibitors, for the effective treatment of cancers has not been achieved. Hence, a thorough understanding of the biology of the mTOR axis in cancer is still needed. It is now recognized that programmed death-ligand 1 (PD-L1) expression on cancer cells is a critical mechanism contributing to immunosuppression and immune escape via interacting with program death-1 (PD-1) on immune cells. This study has revealed a previously undiscovered role of the mTOR complex 1 (mTORC1)/p70 S6 kinase (p70S6K) in the negative regulation of PD-L1 on cancer cells and tissues. We demonstrate that disruption of this signaling pathway with mTOR inhibitors, raptor knockdown or p70S6K inhibitors elevated PD-L1 levels in some lung and other cancer cell lines. Elevation of PD-L1 by inhibition of mTORC1/p70S6K signaling is likely due to suppression of β-TrCP-mediated proteasomal degradation of PD-L1, because inhibition of either mTORC1 or p70S6K facilitated β-TrCP degradation accompanied with enhanced PD-L1 protein stabilization. Our current findings indicate the complexity of the mTOR axis in cancer, which should be considered when targeting this axis for effective cancer treatment. Our findings also suggest a strong scientific rationale for enhancing PD-1/PD-L1-targeted cancer immunotherapy through co-targeting mTORC1/p70S6K signaling.

Topics: A549 Cells; B7-H1 Antigen; Benzoxazoles; beta-Transducin Repeat-Containing Proteins; Cycloheximide; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; HCT116 Cells; HEK293 Cells; Humans; Leupeptins; MCF-7 Cells; Mechanistic Target of Rapamycin Complex 1; Morpholines; Naphthyridines; Neoplasms; Protein Stability; Pyrimidines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Tumor Cells, Cultured

Balanced deoxyribonucleotides pools are essential for cell survival and genome stability. Ribonucleotide reductase is the rate-limiting enzyme for the production of deoxyribonucleotides. We report here that p53 suppresses ribonucleotide reductase subunit 1 (RRM1) and 2 (RRM2) via inhibiting mammalian target of rapamycin complex 1 (mTORC1). In vitro, cancer cell lines and mouse embryonic fibroblast cells were treated with different concentrations of pharmacological inhibitors for different times. In vivo, rhabdomyosarcoma Rh30 cell tumor-bearing mice were treated with rapamycin or AZD8055. Protein levels and phosphorylation status were assessed by immunoblotting and mRNA levels were determined by real time RT-PCR. Pharmacological inhibition of mTORC1 with rapamycin, mTOR kinase with AZD8055 or protein kinase B with MK2206 resulted in decrease of RRM1 and RRM2 in Rh30 cells both in vitro and in mouse tumor xenografts. Moreover, eukaryotic translational initiation factor 4E-binding proteins 1 and 2 double knockout mouse embryonic fibroblast cells demonstrated an elevation of RRM1 and RRM2. Furthermore, down-regulation of mTOR-protein kinase B signaling or cyclin dependent kinase 4 led to decrease of RRM1 and RRM2 mRNAs. In addition, TP53 mutant cancer cells had elevation of RRM1 and RRM2, which was reduced by rapamycin. Importantly, human double minute 2 inhibitor nutlin-3 decreased RRM1 and RRM2 in TP53 wild type rhabdomyosarcoma Rh18 but not in TP53 mutated Rh30 cells. Our data demonstrated that mTOR enhances the cap-dependent protein translation and gene transcription of RRM1 and RRM2. Our findings might provide an additional mechanism by which p53 maintains genome stability.

Topics: A549 Cells; Animals; Cell Line, Tumor; Cells, Cultured; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Mechanistic Target of Rapamycin Complex 1; Mice, Knockout; Mice, SCID; Morpholines; Mutation; Neoplasms; Ribonucleoside Diphosphate Reductase; RNA Interference; Sirolimus; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

AZD8055 is a potent orally available mTOR kinase inhibitor with in vitro and in vivo antitumour activity against a range of tumour types. Preclinical studies showed that AZD8055 induced a dose-dependent pharmacodynamic effect in xenograft models in vivo, but a lack of understanding of the relative contributions of the maximum inhibition of the biomarkers and the duration of inhibition to the antitumour effect, limited the rational design of experiments to optimize the dose and schedules of treatment.. In this study, a mathematical modelling approach was developed to relate pharmacodynamics and antitumour activity using preclinical data generated in mice bearing U87-MG xenografts.. Refinement and validation of the model was carried out in a panel of additional human tumour xenograft models with different growth rates and different sensitivity to AZD8055 (from partial growth inhibition to regression). Finally, the model was applied to accurately predict the efficacy of high, intermittent dosing schedules of AZD8055.. Overall, this new model linking pharmacokinetics, pharmacodynamic biomarkers and efficacy across several tumour xenografts with different sensitivity to AZD8055 was able to identify the optimal dose and route of administration to maximize the antitumour efficacy in preclinical models and its potential for translation into man.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; Mice, Nude; Models, Biological; Morpholines; Neoplasms; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; TOR Serine-Threonine Kinases; Tumor Burden

mTOR is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we had explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here, we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic antitumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation, and proliferation of CD8(+) T cells and natural killer cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/αCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared with that achieved in mice by αCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFα, which played an indispensable role in activation of the observed antitumor immune response. Levels of Th1 cytokines, including interleukin 12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG, and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/αCD40-induced antitumor response was abolished in IFN-γ(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with αCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer.

Topics: Animals; Antibodies; Antineoplastic Agents; CD40 Antigens; CD8-Positive T-Lymphocytes; Dendritic Cells; Humans; Immunotherapy; Interferon-gamma; Interleukin-12; Killer Cells, Natural; Lymphocyte Activation; Macrophage Activation; Mice; Mice, Inbred BALB C; Morpholines; Neoplasms; Neoplasms, Experimental; Sirolimus; TOR Serine-Threonine Kinases

mTOR is a major biological switch, coordinating an adequate response to changes in energy uptake (amino acids, glucose), growth signals (hormones, growth factors) and environmental stress. mTOR kinase is highly conserved through evolution from yeast to man and in both cases, controls autophagy and cellular translation in response to nutrient stress. mTOR kinase is the catalytic component of two distinct multiprotein complexes called mTORC1 and mTORC2. In addition to mTOR, mTORC1 contains Raptor, mLST8 and PRAS40. mTORC2 contains mTOR, Rictor, mSIN1 and Protor-1. mTORC1 activates p70S6K, which in turn phosphorylates the ribosomal protein S6 and 4E-BP1, both involved in protein translation. mTORC2 activates AKT directly by phosphorylating Serine 473. pAKT(S473) phosphorylates TSC2 (tuberin) and inactivates it, preventing its association with TSC1 (hamartin) and the inhibition of Rheb, an activator of mTOR. pAKT also phosphorylates PRAS40, releasing it from the mTORC1 complex, increasing its kinase activity. Finally, AKT regulates FOXO3 phosphorylation, sequestering it in the cytosol in an inactive state.

Topics: Autophagy; Cell Line, Tumor; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Morpholines; Multiprotein Complexes; Neoplasms; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases