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1.
Sci Adv ; 7(21)2021 05.
Article in English | MEDLINE | ID: mdl-34020950

ABSTRACT

Cell division cycle 7 (CDC7), a serine/threonine kinase, plays important roles in DNA replication. We developed a highly specific CDC7 inhibitor, TAK-931, as a clinical cancer therapeutic agent. This study aimed to identify the potential combination partners of TAK-931 for guiding its clinical development strategies. Unbiased high-throughput chemical screening revealed that the highest synergistic antiproliferative effects observed were the combinations of DNA-damaging agents with TAK-931. Functional phosphoproteomic analysis demonstrated that TAK-931 suppressed homologous recombination repair activity, delayed recovery from double-strand breaks, and led to accumulation of DNA damages in the combination. Whole-genome small interfering RNA library screening identified sensitivity-modulating molecules, which propose the experimentally predicted target cancer types for the combination, including pancreatic, esophageal, ovarian, and breast cancers. The efficacy of combination therapy in these cancer types was preclinically confirmed in the corresponding primary-derived xenograft models. Thus, our findings would be helpful to guide the future clinical strategies for TAK-931.


Subject(s)
Neoplasms , Recombinational DNA Repair , Cell Cycle Proteins/metabolism , Cell Line, Tumor , DNA , DNA Damage , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Protein Serine-Threonine Kinases
2.
Eur J Pharmacol ; 807: 21-31, 2017 Jul 15.
Article in English | MEDLINE | ID: mdl-28442322

ABSTRACT

Most cancer cells are characterized by elevated lipid biosynthesis. The rapid proliferation of cancer cells requires de novo synthesis of fatty acids. Stearoyl-CoA desaturase-1 (SCD1), a key enzyme for lipogenesis, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. Therefore, it has been studied as a candidate target for cancer therapy. In this study, we demonstrate the pharmacological properties of T-3764518, a novel and orally available small molecule inhibitor of SCD1. T-3764518 inhibited stearoyl-CoA desaturase-catalyzed conversion of stearoyl-CoA to oleoyl-CoA in colorectal cancer HCT-116 cells and their growth. Further, it slowed tumor growth in an HCT-116 and a mesothelioma MSTO-211H mouse xenograft model. Comprehensive lipidomic analyses revealed that T-3764518 increases the membrane ratio of saturated: unsaturated fatty acids in various lipid species such as phosphatidylcholines and diacylglycerols in both cultured cells and HCT-116 xenografts. Treatment-associated lipidomic changes were followed by activated endoplasmic reticulum (ER) stress responses such as increased immunoglobulin heavy chain-binding protein expression in HCT-116 cells. These T-3764518-induced changes led to an increase in cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptosis. Additionally, bovine serum albumin conjugated with oleic acid, an SCD1 product, prevented cell growth inhibition and ER stress responses by T-3764518, indicating that these outcomes were not attributable to off-target effects. These results indicate that T-3764518 is a promising new anticancer drug candidate.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacology , Oxadiazoles/pharmacology , Oxadiazoles/pharmacokinetics , Pyridazines/pharmacology , Pyridazines/pharmacokinetics , Stearoyl-CoA Desaturase/antagonists & inhibitors , Xenograft Model Antitumor Assays , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Endoplasmic Reticulum Stress/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Fatty Acids/metabolism , HCT116 Cells , Humans , Mice , Oxadiazoles/administration & dosage , Oxadiazoles/metabolism , Pyridazines/administration & dosage , Pyridazines/metabolism , Stearoyl-CoA Desaturase/metabolism
3.
J Med Chem ; 55(7): 3452-78, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-22376051

ABSTRACT

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Thiazoles/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzamides/pharmacokinetics , Benzamides/pharmacology , Benzoates/chemical synthesis , Benzoates/pharmacokinetics , Benzoates/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Molecular Structure , Phosphorylation , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Xenograft Model Antitumor Assays
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