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1.
J Med Chem ; 65(18): 12427-12444, 2022 09 22.
Article in English | MEDLINE | ID: mdl-36066182

ABSTRACT

Kinase fusions involving tropomyosin receptor kinases (TRKs) have been proven to act as strong oncogenic drivers and are therefore recognized as attractive therapeutic targets. We screened an in-house kinase-focused library and identified a promising hit compound with a unique tetracyclic scaffold. Compound 1 showed high TRK selectivity but moderate cell growth inhibitory activity as well as a potential risk of inducing CYP3A4. In this report, chemical modification intended to improve TRK inhibition and avoid CYP3A4 induction enabled us to identify an orally bioavailable, selective, and potent TRK inhibitor 7.


Subject(s)
Neoplasms , Tropomyosin , Cell Proliferation , Cytochrome P-450 CYP3A , Humans , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemistry , Receptor, trkA
2.
Mol Cancer Ther ; 17(12): 2519-2529, 2018 12.
Article in English | MEDLINE | ID: mdl-30242093

ABSTRACT

Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.


Subject(s)
Benzofurans/pharmacology , Neoplasms/pathology , Oncogene Proteins, Fusion/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Animals , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Female , Humans , Mice, Inbred BALB C , Mice, Nude , Mutation/genetics , Protein Kinases/chemistry , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
3.
Cancer Lett ; 409: 116-124, 2017 11 28.
Article in English | MEDLINE | ID: mdl-28923400

ABSTRACT

Microphthalmia-associated transcription factor (MITF) is expressed in melanomas and has a critical role in melanocyte development and transformation. Because inhibition of MITF inhibits cell growth in melanoma, MITF is a potential therapeutic target molecule. Here, we report the identification of CH6868398, which has a novel chemical structure and suppresses MITF expression at the protein level in melanoma cells. CH6868398 showed cell growth inhibition activity against MITF-dependent melanoma cells both with and without BRAF mutation and also exhibited anti-tumor efficacy in a melanoma xenograft model. Because selective BRAF inhibitors are standard therapeutics for BRAF-mutated melanoma, we investigated the effect of CH6868398 with a BRAF inhibitor, PLX4720, on cell growth inhibition. The addition of CH6868398 enhanced the cell growth inhibition activity of PLX4720 in melanoma cell lines. Furthermore, combination of CH6868398 and PLX4720 efficiently suppressed MITF protein and enhanced cleavage of Caspase3 and poly (ADP-ribose) polymerase (PARP) in melanoma cell lines. These data support the therapeutic potential of CH6868398 as an anti-melanoma agent that reduces MITF protein levels in combination with BRAF inhibitors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Melanoma/drug therapy , Microphthalmia-Associated Transcription Factor/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , Female , Humans , Indoles/pharmacology , Melanoma/enzymology , Melanoma/genetics , Melanoma/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Protein Kinase Inhibitors/administration & dosage , Random Allocation , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays
4.
Bioorg Med Chem ; 20(3): 1271-80, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22225917

ABSTRACT

Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Haplorhini , Humans , Lung Neoplasms/drug therapy , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolism
5.
J Med Chem ; 54(18): 6286-94, 2011 Sep 22.
Article in English | MEDLINE | ID: mdl-21823617

ABSTRACT

9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.


Subject(s)
Antineoplastic Agents/chemical synthesis , Carbazoles/chemical synthesis , Piperazines/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , In Vitro Techniques , Macaca fascicularis , Male , Mice , Mice, SCID , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous
6.
Cancer Cell ; 19(5): 679-90, 2011 May 17.
Article in English | MEDLINE | ID: mdl-21575866

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Carbazoles/pharmacology , Drug Resistance, Neoplasm , Neoplasms/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Carbazoles/administration & dosage , Carbazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Humans , Mice , Mice, Nude , Mice, SCID , Models, Molecular , Mutation , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/pathology , Piperidines/administration & dosage , Piperidines/chemistry , Protein Conformation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Recombinant Fusion Proteins/antagonists & inhibitors , Recombinant Fusion Proteins/metabolism , Time Factors , Transfection , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
7.
Bioorg Med Chem Lett ; 21(12): 3788-93, 2011 Jun 15.
Article in English | MEDLINE | ID: mdl-21561771

ABSTRACT

Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivatives as potent ALK inhibitors. Among them, compound 27 showed strong cytotoxicity against KARPAS-299 with an IC(50) value of 21 nM and significant antitumor efficacy in ALK fusion-positive blood and solid cancer xenograft models in mice without body weight loss.


Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Discovery , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Tetracyclines/chemical synthesis , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Disease Models, Animal , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Tetracyclines/chemistry , Tetracyclines/pharmacology
8.
Curr Eye Res ; 33(11): 1002-10, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19085383

ABSTRACT

PURPOSE: To select a novel orally administered VEGFR-2 (KDR/flk-1) specific tyrosine kinase inhibitor in a murine model of choroidal neovascularization (CNV). METHODS: From a compound library, potent VEGFR2 inhibitors were selected by VEGF-induced phosphorylation of VEGFR-2 and RAF kinases and the proliferation analysis by HUVEC cultures and in vitro tube formation assay. CNV was induced in C57/BL6 mice using diode laser photocoagulation. The antiangiogenic effect of selected compounds was assessed by angiographic examination, in which extent of fluorescein leakage was scored and histological analysis, allowing for measurement of CNV membrane under light microscope. In addition, C57/BL6 mice were treated with daily oral administration of selected compounds for 14 days and body weights were measured. RESULTS: Six compounds that potently inhibited VEGFR-2 were selected for further investigation. Selected compounds-treated conditions showed a dose-dependent inhibition of phosphorylation of VEGFR-2 tyrosine kinase with an IC50 of 0.0022 to 0.098 microm. Selected compounds did not inhibit the HCT116 proliferation but did demonstrate a strong inhibition effect for VEGFR-2 dependant HUVEC (IC50=0.0018 to 0.058 microm). Selected compounds treatment also resulted in a dose-dependent attenuation of in vitro tube formation. In the murine CNV model, #0451 is the most effective compound. The intensity of fluorescein leakage was significantly lower in doses of 12.5, 25, 50, and 100 mg/kg #0451-treated eyes compared to controls. Histologically, CNV membrane volumes were significantly reduced in #0451-treated eyes in a dose-dependent manner. At therapeutic doses of 100 mg/kg or less, there was no significant weight loss between the treated and untreated groups. CONCLUSION: Oral administration of #0451, a novel VEGFR-2 (KDR/flk-1)-specific tyrosine kinase inhibitor, demonstrates anti-angiogenic effects in our murine model of CNV. #0451 may be useful to treat the choroidal neovascularization associated with AMD.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Choroidal Neovascularization/physiopathology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/administration & dosage , Angiography , Animals , Cell Proliferation/drug effects , Cells, Cultured , Choroidal Neovascularization/diagnostic imaging , Choroidal Neovascularization/metabolism , Dose-Response Relationship, Drug , Endothelial Cells/cytology , Fluorescein , Fluorescent Dyes , Humans , Mice , Mice, Inbred C57BL , Phosphorylation/drug effects , Vascular Endothelial Growth Factor Receptor-2/metabolism
9.
Bioorg Med Chem Lett ; 17(8): 2241-5, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17306533

ABSTRACT

DNA microarray analysis comparing human tumor tissues with normal tissues including hematopoietic progenitor cells resulted in identification of membrane dipeptidase as a prodrug activation enzyme. Novel prodrugs of 2'-deoxy-2'-methylidenecytidine (DMDC) including compound 23 that are activated by membrane dipeptidase (MDP) preferentially in tumor tissue were designed and synthesized to generate the active drug, DMDC, after hydrolysis of the dipeptide bond followed by spontaneous cyclization of the promoiety.


Subject(s)
Antineoplastic Agents/chemical synthesis , Deoxycytidine/analogs & derivatives , Dipeptidases/metabolism , Drug Design , Gene Expression Regulation, Neoplastic , Prodrugs/chemical synthesis , Prodrugs/metabolism , Antineoplastic Agents/pharmacokinetics , Deoxycytidine/chemistry , Deoxycytidine/metabolism , Deoxycytidine/pharmacokinetics , Dipeptidases/genetics , Humans , Hydrolysis , Membrane Proteins , Neoplasm Proteins/metabolism , Oligonucleotide Array Sequence Analysis , Structure-Activity Relationship , Tumor Cells, Cultured
10.
Bioorg Med Chem ; 14(4): 1143-59, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16249087

ABSTRACT

In this study, 172 diacylhydrazine analogs were examined for their ability to activate an ecdysone (molting hormone)-dependent reporter gene in a silkworm (Bombyx mori) cell-based high-throughput screening assay. The measured EC(50) values (concentration required to cause an effect in 50% of the cells) were used to construct a 3-D QSAR model that describes the ecdysone agonist activities of the diacylhydrazine analogs. Of these compounds, 14 exhibited no activity and were excluded from the 3-D QSAR analysis. The resulting equation described approximately 74% of the activity for 158 compounds. The final equation consisted of 42% electrostatic and 58% steric effects (r(2) = 0.74 and q(2) = 0.45). Comparative molecular field analysis (CoMFA) was used to visualize the steric and electrostatic potential fields that were favorable and unfavorable for biological activity. Of particular interest was the observation that the hydrophobic parameter (logP) was not necessary for describing the observed activities, although previous studies have cited the importance of hydrophobic parameters in both classical and 3-D QSAR analyses of these compounds. Modeling studies of the B. mori ecdysone receptor supported the observed physicochemical parameters required for activity reported by the CoMFA models. Comparison of the present analysis with those performed using other lepidopteran assay systems evidenced a high degree of correlation (r(2) = 0.81 for a Sf-9 cell-based assay and r(2) = 0.89 for a Chilo suppressalis integument-based assay), indicating that it is valid to compare the results generated with the B. mori cell-based system to those generated with previous lepidopteran assays. This novel assay system is amendable to a high-throughput screening format and should greatly increase our ability to discover novel agonists of molting hormone (ecdysone) activity.


Subject(s)
Drug Evaluation, Preclinical/methods , Ecdysone/agonists , Ecdysone/pharmacology , Genes, Reporter/genetics , Amino Acid Sequence , Animals , Conserved Sequence , Ecdysone/chemistry , Ecdysone/metabolism , Humans , Hydrazines/chemistry , Hydrazines/pharmacology , Hydrophobic and Hydrophilic Interactions , Ligands , Models, Molecular , Molecular Sequence Data , Molecular Structure , Protein Structure, Tertiary , Quantitative Structure-Activity Relationship , Receptors, Steroid/agonists , Receptors, Steroid/chemistry , Receptors, Steroid/metabolism , Sequence Alignment
11.
Bioorg Med Chem Lett ; 13(5): 867-72, 2003 Mar 10.
Article in English | MEDLINE | ID: mdl-12617910

ABSTRACT

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/chemical synthesis , Deoxycytidine/pharmacokinetics , Oxidoreductases/antagonists & inhibitors , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Uracil/analogs & derivatives , Administration, Oral , Animals , Capecitabine , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cytidine Deaminase/metabolism , Dihydrouracil Dehydrogenase (NADP) , Drug Design , Drug Stability , Esterases/metabolism , Female , Fluorouracil/blood , Fluorouracil/pharmacokinetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Mice , Prodrugs/administration & dosage , Thymidine Phosphorylase/metabolism , Tissue Distribution , Uracil/pharmacokinetics , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/metabolism , Xenograft Model Antitumor Assays
12.
Bioorg Med Chem Lett ; 13(2): 191-6, 2003 Jan 20.
Article in English | MEDLINE | ID: mdl-12482421

ABSTRACT

A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , Antifungal Agents/pharmacokinetics , Aspergillosis/drug therapy , Aspergillosis/microbiology , Biotransformation , Candidiasis/drug therapy , Candidiasis/microbiology , Chemical Phenomena , Chemistry, Physical , Drug Design , Half-Life , Haplorhini , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Models, Molecular , Molecular Conformation , Prodrugs/pharmacokinetics , Rats , Solubility , Solvents , Triazoles/pharmacokinetics , Water
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