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1.
Nat Commun ; 12(1): 4671, 2021 08 03.
Article in English | MEDLINE | ID: mdl-34344863

ABSTRACT

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Neoplastic Stem Cells/drug effects , Nitrobenzenes/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Thiazines/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Mice , Neoplastic Stem Cells/pathology , Nitrobenzenes/chemistry , Nitrobenzenes/pharmacology , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , Thiazines/chemistry , Thiazines/pharmacology , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays , Dyrk Kinases
2.
Oncotarget ; 9(102): 37753-37765, 2018 Dec 28.
Article in English | MEDLINE | ID: mdl-30701029

ABSTRACT

Overexpression and constitutive activation of CYCLIN D1 and Casein Kinase 2 are common features of many hematologic malignancies, including mantle cell lymphoma (MCL) and leukemias such as T-cell acute lymphoblastic leukemia (T-ALL). Although both CK2 and CDK4 inhibitors have shown promising results against these tumor types, none of these agents have achieved objective responses in the clinic as monotherapies. Because both proteins play key roles in these and other hematological malignancies, we have analyzed the therapeutic potential of ON108110, a novel dual specificity ATP-competitive inhibitor of protein kinase CK2 as well as CDK4/6 in MCL and T-ALL. We show that in cell growth inhibition assays, MCL and T-ALL cell lines exhibited increased sensitivity to ON108110 when compared to other tumor types. Treatment with ON108110 reduced the level of phosphorylated RB-family proteins. In addition, ON108110 treatment resulted in concentration dependent inhibition of PTEN phosphorylation and a concomitant decrease in PI3K-AKT signaling mediated by CK2. Accordingly, cells treated with ON108110 rapidly accumulated in the G0/G1 stage of the cell cycle as a function of increasing concentration followed by rapid onset of apoptosis. Together, these results indicate that dual inhibition of CK2 and CDK4/6 may be an efficient treatment of MCL and T-ALLs displaying upregulation of CK2/PI3K and CDK4 signaling pathways.

3.
J Med Chem ; 57(3): 578-99, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24417566

ABSTRACT

The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Repressor Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Heterografts , Humans , Mice , Mice, Nude , Molecular Docking Simulation , Neoplasm Transplantation , Protein Kinases , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship
4.
Anticancer Agents Med Chem ; 13(9): 1460-6, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24102269

ABSTRACT

Hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) are transcription factors and are activated in response to hypoxia. Both HIF-1α and STAT3 regulate various aspects of cancer biology such as cell survival, proliferation, angiogenesis etc. and are constitutively expressed in a wide range of human cancers. In the last decade, over expression of HIF-1α and STAT3 has been demonstrated in many common human cancers, thereby emerging as highly compelling anticancer targets for drug discovery. We herein report the design and synthesis of new imidazopyridine based potent dual inhibitors of HIF-1α and STAT3 pathways. The lead compound of this series P3971 has been identified as a potent inhibitor of HIF-1α (200 nM) and STAT3 (350 nM) with significant antiproliferative activity against various cancer cell lines. Moreover, P3971 was also found to be orally efficacious in HCT116 (colon cancer) and H460 (lung cancer) xenograft mice models.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Imidazoles/pharmacology , Neoplasms/drug therapy , STAT3 Transcription Factor/antagonists & inhibitors , Sulfonamides/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Imidazoles/chemical synthesis , Imidazoles/chemistry , Mice , Mice, SCID , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Tumor Cells, Cultured
5.
J Med Chem ; 56(13): 5562-86, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-23750455

ABSTRACT

A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Microtubules/drug effects , Neoplasms/drug therapy , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Biological Availability , Blood-Brain Barrier/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , HCT116 Cells , Humans , K562 Cells , MCF-7 Cells , Mice , Mice, Nude , Microtubules/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Polymerization/drug effects , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Tubulin/metabolism , Tumor Burden/drug effects
6.
BMC Cancer ; 11: 338, 2011 Aug 05.
Article in English | MEDLINE | ID: mdl-21819554

ABSTRACT

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. It is essential for angiogenesis and is associated with tumor progression and overexpression of HIF-1α has been demonstrated in many common human cancers. Therefore, HIF-1α is one of the most compelling anticancer targets. METHODS: To identify HIF-1α inhibitors, luciferase reporter gene assay under hypoxia and normoxia was used. Detailed studies such as western blotting, RT-PCR, immunofluorescence were carried out to elucidate its mechanism of action. Antiangiogenic activity of P3155 was demonstrated by migration assay and tube formation assay. Efficacy study of P3155 was performed on PC-3 xenograft model. RESULTS: P3155 showed specific HIF-1α inhibition with IC50 of 1.4 µM under hypoxia. It suppressed HIF-1α expression as well as PI3K/Akt pathway and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor (VEGF). P3155 in combination with HIF-1α siRNA showed significant synergistic effect. In addition, it demonstrated significant in vivo efficacy and antiangiogenic potential in prostate cancer cell lines. CONCLUSION: We have identified a novel HIF-1α inhibitor P3155 that also modulates PI3K/Akt pathway, which may contribute to its significant in vitro and in vivo antitumor activity.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/drug therapy , Pyridines/pharmacology , Pyrimidines/pharmacology , Animals , Cell Growth Processes/drug effects , Cell Hypoxia/physiology , Cell Line, Tumor , Cell Movement/drug effects , Dose-Response Relationship, Drug , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Mice , Neovascularization, Pathologic/drug therapy , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Signal Transduction/drug effects , Topotecan/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor Assays
7.
Bioorg Med Chem Lett ; 20(22): 6426-9, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20932758

ABSTRACT

Hypoxia-inducible factor-1α (HIF-1α) is a critical regulatory protein of cellular response to hypoxia, and regulates the transcription of many genes involved in key aspects of cancer biology, including immortalization, maintenance of stem cell pools, cellular dedifferentiation, vascularization, and invasion/metastasis. HIF-1α has been implicated in the regulation of genes involved in angiogenesis, for example, VEGF and is associated with tumor progression. In the last decade, over expression of HIF-1α has been demonstrated in many common human cancers and emerging as a validated target for anticancer drug discovery. Here we report the discovery of newly designed and synthesized pyridylpyrimidine based potent and selective inhibitors of HIF-1α. P2630 has been found as potent antiproliferative, antiangiogenic and orally efficacious compound in PC-3 xenograft mice model.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Pyridines/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemistry , Cells, Cultured , Drug Screening Assays, Antitumor , Humans , Mice , Mice, SCID
8.
J Biol Chem ; 284(21): 14126-35, 2009 May 22.
Article in English | MEDLINE | ID: mdl-19321444

ABSTRACT

We have previously shown that SV40 small t antigen (st) cooperates with deregulated cyclin E to activate CDK2 and bypass quiescence in normal human fibroblasts (NHF). Here we show that st expression in serum-starved and density-arrested NHF specifically induces up-regulation and loading of CDC6 onto chromatin. Coexpression of cyclin E results in further accumulation of CDC6 onto chromatin concomitantly with phosphorylation of CDK2 on Thr-160 and CDC6 on Ser-54. Investigation of the mechanism leading to CDC6 accumulation and chromatin loading indicates that st is a potent inducer of cdc6 mRNA expression and increases CDC6 protein stability. We also show that CDC6 expression in quiescent NHF efficiently promotes cyclin E loading onto chromatin, but it is not sufficient to activate CDK2. Moreover, we show that CDC6 expression is linked to phosphorylation of the activating T loop of CDK2 in serum-starved NHF stimulated with mitogens or ectopically expressing cyclin E and st. Our data suggest a model where the combination of st and deregulated cyclin E result in cooperative and coordinated activation of both an essential origin licensing factor, CDC6, and an activity required for origin firing, CDK2, resulting in progression from quiescence to S phase.


Subject(s)
Antigens, Polyomavirus Transforming/metabolism , Cell Cycle Proteins/metabolism , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/metabolism , Fibroblasts/cytology , Fibroblasts/enzymology , Nuclear Proteins/metabolism , Oncogene Proteins/metabolism , Cell Cycle/drug effects , Cell Cycle Proteins/genetics , Cell Line , Chromatin/metabolism , E2F Transcription Factors/metabolism , Enzyme Activation/drug effects , Fibroblasts/drug effects , Humans , Mitogens/pharmacology , Models, Biological , Nuclear Proteins/genetics , Phosphorylation/drug effects , Phosphothreonine/metabolism , Protein Stability/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Telomerase/metabolism , Up-Regulation/drug effects
9.
Bioorg Med Chem Lett ; 18(12): 3603-6, 2008 Jun 15.
Article in English | MEDLINE | ID: mdl-18501601

ABSTRACT

We herein report the design and synthesis of furoquinoline based novel molecules (16-36) and their in vitro multiple targeted inhibitory potency against PI3K/Akt phosphorylation and mTOR using cell based and cell-free kinase assay. In particular, compound 23 in addition to PI3K-mTOR inhibitory potency, it has shown potent inhibition of hypoxia-induced accumulation of HIF-1alpha protein in U251-HRE cell line. The inhibitory activities of compound 23 were confirmed by Western blot analysis, using human non-small cell lung carcinoma H-460 cell line and glioblastoma U251 cell lines.


Subject(s)
Enzyme Inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinases/drug effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Blotting, Western , Cell Line, Tumor , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Protein Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Signal Transduction/drug effects , Stereoisomerism , Structure-Activity Relationship , TOR Serine-Threonine Kinases
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