5-(4-amino-1-propan-2-yl-3-pyrazolo[3-4-d]pyrimidinyl)-1-3-benzoxazol-2-amine has been researched along with Disease-Models--Animal* in 12 studies
1 review(s) available for 5-(4-amino-1-propan-2-yl-3-pyrazolo[3-4-d]pyrimidinyl)-1-3-benzoxazol-2-amine and Disease-Models--Animal
1 trial(s) available for 5-(4-amino-1-propan-2-yl-3-pyrazolo[3-4-d]pyrimidinyl)-1-3-benzoxazol-2-amine and Disease-Models--Animal
11 other study(ies) available for 5-(4-amino-1-propan-2-yl-3-pyrazolo[3-4-d]pyrimidinyl)-1-3-benzoxazol-2-amine and Disease-Models--Animal
| Article | Year |
|---|---|
Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC. Topics: Anilides; Animals; Benzoxazoles; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Female; Humans; Liver Neoplasms; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; PTEN Phosphohydrolase; Pyridines; Pyrimidines; Thiazoles; Treatment Outcome; Tumor Burden | 2021 |
Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors.
When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection. Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection | 2020 |
mTOR inhibitor INK128 attenuates dextran sodium sulfate-induced colitis by promotion of MDSCs on Treg cell expansion.
Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in pathogenesis of inflammatory bowel diseases (IBDs). INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in IBD are unclear. Here, we showed that the INK128 treatment enhanced the resistance of mice to dextran sodium sulfate (DSS)-induced colitis and inhibited the differentiation of MDSCs into macrophages. Moreover, interferon (IFN)-α level was elevated in INK128-treated colitis mice. When stimulated with IFN-α in vitro, MDSCs showed a superior immunosuppression activity. Of note, the regulatory T cells (Tregs) increased but Th1 cells decreased in INK128-treated colitis mice. These results indicate that mTOR inhibitor INK128 attenuates DSS-induced colitis via Treg expansion promoted by MDSCs. Our work provides a new evidence that INK128 is potential to be a therapeutic drug on DSS-induced colitis via regulating MDSCs as well as maintaining Treg expansion. Topics: Animals; Benzoxazoles; Cell Communication; Cell Proliferation; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Female; Lymphocyte Activation; Macrophages; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Protein Kinase Inhibitors; Pyrimidines; RAW 264.7 Cells; Signal Transduction; T-Lymphocytes, Regulatory; Th1 Cells; TOR Serine-Threonine Kinases | 2019 |
Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma.
Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Benzoxazoles; Cell Cycle Checkpoints; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; Heterografts; Humans; Inhibitory Concentration 50; Lymphoma, Primary Effusion; Mice; Neoplasm Transplantation; Pyrimidines; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome | 2019 |
mTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease.
Mechanistic target of rapamycin (mTOR) has been shown to play an important role in red blood cell physiology, with inhibition of mTOR signalling leading to alterations in erythropoiesis. To determine if mTOR inhibition would improve anaemia in sickle cell disease (SCD), mice with SCD were treated with the dual mTORC1/2 inhibitor, INK128. One week after daily oral drug treatment, erythrocyte count, haemoglobin, and haematocrit were all significantly increased while reticulocyte counts were reduced. These parameters remained stable during 3 weeks of treatment. Similar effects were observed following oral treatment with the mTORC1 inhibitor, sirolimus. Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice. Following middle cerebral artery occlusion, stroke size was reduced in SCD mice treated with sirolimus. In conclusion, mTOR inhibition is protective against anaemia and organ damage in a murine model of SCD. Topics: Anemia; Anemia, Sickle Cell; Animals; Benzoxazoles; Disease Models, Animal; Erythrocytes; Hematocrit; Hemoglobins; Mice; Pyrimidines; Sirolimus; Splenomegaly; TOR Serine-Threonine Kinases | 2016 |
MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma.
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in multiple sarcoma subtypes. First-generation allosteric inhibitors of mTORC1 (rapalogues) have been extensively tested with great preclinical promise, but have had limited clinical utility. Here, we report that MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2 and has potent in vitro and in vivo antitumor activity in multiple sarcoma subtypes. In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration-dependent fashion and shows striking antiproliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma. Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone. In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg b.i.d. t.i.w.). At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and Ewing sarcoma models. In addition, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma. Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Apoptosis; Benzoxazoles; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Down-Regulation; Female; Humans; Inhibitory Concentration 50; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice, Nude; Multiprotein Complexes; Osteosarcoma; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Sirolimus; Substrate Specificity; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays | 2015 |
The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent.
The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK-128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK-128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT-29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials. Topics: Animals; Antineoplastic Agents; Apoptosis; Benzoxazoles; Cadherins; Carrier Proteins; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Fluorouracil; HT29 Cells; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Microfilament Proteins; Multiprotein Complexes; Protein Kinase Inhibitors; Pyrimidines; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays | 2015 |
Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice.
HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains. Topics: Adenosine Triphosphate; Allosteric Site; Animals; Anti-HIV Agents; Benzoxazoles; Catalytic Domain; CD4-Positive T-Lymphocytes; Cell Proliferation; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; HIV Infections; HIV-1; Humans; Interleukin-2; Leukocytes, Mononuclear; Lymphocytes; Mice; NF-kappa B; Pyrimidines; TOR Serine-Threonine Kinases; Transcription, Genetic | 2015 |
Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.
Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1-mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1-mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1-mutant adenocarcinomas and squamous cell tumors. Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzoxazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Models, Animal; Humans; Immunohistochemistry; Lung Neoplasms; Mice; Phenformin; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins p21(ras); Pyrimidines; Stress, Physiological | 2015 |
Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia.
The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase whose activity contributes to leukemia proliferation and survival. Compounds targeting the mTOR active site inhibit rapamycin-resistant functions and have enhanced anticancer activity in mouse models. MLN0128 (formerly known as INK128) is a novel, orally active mTOR kinase inhibitor currently in clinical development. Here, we evaluated MLN0128 in preclinical models of B-cell acute lymphoblastic leukemia (B-ALL). MLN0128 suppressed proliferation of B-ALL cell lines in vitro and reduced colony formation by primary human leukemia cells from adult and pediatric B-ALL patients. MLN0128 also boosted the efficacy of dasatinib (DA) in Philadelphia Chromosome-positive (Ph+) specimens. In a syngeneic mouse model of lymphoid BCR-ABL+ disease, daily oral dosing of MLN0128 rapidly cleared leukemic outgrowth. In primary xenografts of Ph+ B-ALL specimens, MLN0128 significantly enhanced the efficacy of DA. In non-Ph B-ALL xenografts, single agent MLN0128 had a cytostatic effect that was most pronounced in mice with low disease burden. In all in vivo models, MLN0128 was well tolerated and did not suppress endogenous bone marrow proliferation. These findings support the rationale for clinical testing of MLN0128 in both adult and pediatric B-ALL and provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors. Topics: Adult; Animals; Benzoxazoles; Bone Marrow; Cell Proliferation; Colony-Forming Units Assay; Disease Models, Animal; Female; Flow Cytometry; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrimidines; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Cells, Cultured | 2013 |
Equivalent benefit of rapamycin and a potent mTOR ATP-competitive inhibitor, MLN0128 (INK128), in a mouse model of tuberous sclerosis.
Tuberous sclerosis complex (TSC) is a hamartoma syndrome in which brain, renal, and lung tumors develop and cause both morbidity and death. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1. Rapamycin and related drugs have been shown to have clinical benefit for these tumors in patients with TSC and those with sporadic forms of TSC-related neoplasms. However, lifelong therapy seems to be required, as tumors are not eliminated by this treatment. We examined the potential benefit of MLN0128, a novel potent mTOR ATP-competitive inhibitor, as a therapeutic strategy for renal cystadenomas that develop in A/J Tsc2(+/-) mice. Rapamycin given by intraperitoneal injection at 3 mg/kg 3 times per week, and MLN0128 given by gavage at 0.75 mg/kg 5 times per week had equivalent effects in suppressing tumor development during a 4-week treatment period, with an approximate 99% reduction in microscopic tumor cell volume. Marked reduction in activation of mTOR complex (mTORC)1 and blockade of cell growth was seen with both drugs, whereas only MLN0128 treatment had effects in blocking mTORC2 and 4EBP1 phosphorylation. However, when either drug was discontinued and mice were observed for two additional months, there was dramatic recovery of tumor growth, with extensive proliferation. Hence, longlasting tumor growth control is not achieved with transient treatment with either drug, and MLN0128 and rapamycin have equivalent therapeutic benefit in this mouse model. Differences in side-effect profiles might make MLN0128 more attractive for treatment of patients with TSC-related tumors, but will require additional study in humans. Topics: Animals; Benzoxazoles; Cell Growth Processes; Cystadenoma; Disease Models, Animal; Immunohistochemistry; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Phosphorylation; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis | 2013 |