Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 48
Filter
Add more filters










Publication year range
1.
Oncol Lett ; 21(6): 473, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33907583

ABSTRACT

Since bromodomain containing 4 (brd4) has been considered as a prominent cancer target, numerous attempts have been made to develop potent brd4 bromodomain inhibitors. The present study provided a novel chemical scaffold which inhibited brd4 activity. Mid-throughput screening against brd4 bromodomain was performed using alpha-screen and homogeneous time-resolved fluorescence assays. Furthermore, cell cytotoxicity and xenograft assays were performed to examine if the compound was effective both in vitro and in vivo. As a result, it was revealed that compounds having naphthalene-1,4-dione scaffold inhibited the binding of bromodomain to acetylated histone. The compounds with naphthalene-1,4-dione had cytotoxic effects against the Ty82 cell line, a NUT midline carcinoma cell line, whose proliferation is dependent on brd4 activity. A10, one of the compounds with naphthalene-1,4-dione scaffold, also exhibited tumor growth inhibition effects in the xenograft assay. In addition, the compounds exhibited cytotoxic effects against gastric cancer cell lines which were resistant to I-BET-762, a BET bromodomain inhibitor. In conclusion, the novel scaffold to suppress brd4 activity was effective against cancer cells both in vitro and in vivo.

2.
Eur J Med Chem ; 208: 112769, 2020 Dec 15.
Article in English | MEDLINE | ID: mdl-32961381

ABSTRACT

Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Piperazines/therapeutic use , Proteolysis/drug effects , Receptors, Androgen/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Humans , Male , Mice, Inbred ICR , Mice, SCID , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Receptors, Androgen/chemistry , Xenograft Model Antitumor Assays
3.
Eur J Med Chem ; 166: 65-74, 2019 Mar 15.
Article in English | MEDLINE | ID: mdl-30684871

ABSTRACT

Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.


Subject(s)
Immunologic Factors/pharmacology , Peptide Hydrolases/metabolism , Proteolysis/drug effects , Adaptor Proteins, Signal Transducing , Animals , Cell Line, Tumor , Female , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , Mice , Piperidones/chemical synthesis , Piperidones/chemistry , Piperidones/pharmacology , Ubiquitin-Protein Ligases , Xenograft Model Antitumor Assays
4.
Biochem Biophys Res Commun ; 505(2): 542-547, 2018 10 28.
Article in English | MEDLINE | ID: mdl-30274779

ABSTRACT

Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model.


Subject(s)
Anaplastic Lymphoma Kinase/metabolism , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Ligands , Mice, Inbred BALB C , Mice, Nude , Neoplasms/drug therapy , Neoplasms/pathology , Oncogene Proteins, Fusion/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Proteolysis , Pyrimidines/chemistry , Sulfones/chemistry , Von Hippel-Lindau Tumor Suppressor Protein/metabolism
5.
Biochem Biophys Res Commun ; 503(2): 882-887, 2018 09 05.
Article in English | MEDLINE | ID: mdl-29928885

ABSTRACT

Bromodomain-containing protein 4 (Brd4) is known to play a key role in tumorigenesis. It binds acetylated histones to regulate the expression of numerous genes. Because of the importance of brd4 in tumorigenesis, much research has been undertaken to develop brd4 inhibitors with therapeutic potential. As a result, various scaffolds for bromodomain inhibitors have been identified. To discover new scaffolds, we performed mid-throughput screening using two different enzyme assays, alpha-screen and ELISA. We found a novel bromodomain inhibitor with a unique scaffold, aristoyagonine. This natural compound showed inhibitory activity in vitro and tumor growth inhibition in a Ty82-xenograft mouse model. In addition, we tested Brd4 inhibitors in gastric cancer cell lines, and found that aristoyagonine exerted cytotoxicity not only in I-BET-762-sensitive cancer cells, but also in I-BET-762-resistant cancer cells. This is the first paper to describe a natural compound as a Brd4 bromodomain inhibitor.


Subject(s)
Biological Products/pharmacology , High-Throughput Screening Assays/methods , Isoquinolines/pharmacology , Nuclear Proteins/antagonists & inhibitors , Transcription Factors/antagonists & inhibitors , Animals , Cell Cycle Proteins , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Mice, Inbred BALB C , Mice, Nude , Neoplasms/pathology , Neoplasms/prevention & control , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
6.
PLoS One ; 13(6): e0198347, 2018.
Article in English | MEDLINE | ID: mdl-29874279

ABSTRACT

Gastric cancer is a malignancy that has a high mortality rate. Although progress has been made in the treatment of gastric cancer, many patients experience cancer recurrence and metastasis. Folate receptor 1 (FOLR1) is overexpressed on the cell surface in over one-third of gastric cancer patients, but rarely is expressed in normal tissue. This makes FOLR1 a potential target for chimeric antigen receptor (CAR) T cell immunotherapy, although the function of FOLR1 has not been elucidated. CAR are engineered fusion receptor composed of an antigen recognition region and signaling domains. T cells expressing CAR have specific activation and cytotoxic effects against cancer cells containing the target antigen. In this study, we generated a CAR that targets FOLR1 composed of a single-chain variable fragment (scFv) of FOLR1 antibody and signaling domains consisting of CD28 and CD3ζ. Both FOLR1-CAR KHYG-1, a natural killer cell line, and FOLR1-CAR T cells recognized FOLR1-positive gastric cancer cells in a MHC-independent manner and induced secretion of various cytokines and caused cell death. Conclusively, this is the first study to demonstrate that CAR KHYG-1/T cells targeting FOLR1 are effective against FOLR1-positive gastric cancer cells.


Subject(s)
Folate Receptor 1/immunology , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/immunology , Stomach Neoplasms/therapy , T-Lymphocytes/transplantation , Animals , Cell Line, Tumor , Cell Proliferation , Cell Survival , Humans , Jurkat Cells , K562 Cells , Mice , Receptors, Antigen, T-Cell/immunology , Recombinant Fusion Proteins/immunology , Stomach Neoplasms/immunology , T-Lymphocytes/immunology , Xenograft Model Antitumor Assays
7.
Arch Pharm Res ; 41(1): 46-56, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29103140

ABSTRACT

Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (IC50) of 60 nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.


Subject(s)
Antineoplastic Agents/pharmacology , Indazoles/pharmacology , Nuclear Proteins/antagonists & inhibitors , Transcription Factors/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle Proteins , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Structure-Activity Relationship , Transcription Factors/genetics , Transcription Factors/metabolism
9.
Bioorg Med Chem Lett ; 27(10): 2185-2191, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28385505

ABSTRACT

In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.


Subject(s)
Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Lung Neoplasms/drug therapy , Mice , Mice, SCID , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/toxicity , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Pyrimidines/toxicity , Receptor Protein-Tyrosine Kinases/metabolism , Transplantation, Heterologous
10.
Eur J Med Chem ; 126: 536-549, 2017 Jan 27.
Article in English | MEDLINE | ID: mdl-27915169

ABSTRACT

The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC50 of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/chemistry , Pyrazoles , Pyridines , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/drug effects , Sulfones/pharmacology , Amines/chemistry , Anaplastic Lymphoma Kinase , Animals , Crizotinib , Drug Resistance, Neoplasm/genetics , Heterografts/drug effects , Humans , Mice , Mutation , Piperidines/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Receptor Protein-Tyrosine Kinases/genetics , Sulfones/chemistry , Sulfones/pharmacokinetics
11.
Cancer Lett ; 374(2): 272-8, 2016 May 01.
Article in English | MEDLINE | ID: mdl-26923554

ABSTRACT

Ceritinib, an ALK inhibitor, was hurriedly approved by the US FDA last year, and demonstrates impressive results in EML4-ALK positive patients. To get a superior ALK inhibitor, we synthesized several ceritinib derivatives with minor modifications to the phenylpiperidine moiety. Biochemical and cellular assays demonstrated the improved activity of KRCA-386 over that of ceritinib. KRCA-386 has superior inhibitory activity against ALK mutants commonly found in crizotinib-resistant patients. Particularly, KRCA-386 has considerably greater activity than ceritinib against the G1202R mutant, one of the most challenging mutations to overcome. The cell cycle analysis indicates that ALK inhibitors induce G1/S arrest, resulting in apoptosis. The in vivo xenograft data also demonstrate that KRCA-386 is significantly better than ceritinib. KRCA-386 dosed at 25 mpk caused 105% tumor growth inhibition (TGI) compared to 72% TGI with ceritinib dosed at 25 mpk. (n = 8, P = 0.010) The kinase profiling assay revealed that several kinases, which are known to be critical for tumor growth, are inhibited by KRCA-386, but not by ceritinib. We anticipate that this characteristic of KRCA-386 enhances its in vivo efficacy. In addition, KRCA-386 shows excellent blood brain barrier penetration compared to ceritinib. These results suggest that KRCA-386 could be useful for crizotinib-resistant patients with brain metastases.


Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/enzymology , Oncogene Proteins, Fusion/biosynthesis , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Blood-Brain Barrier/metabolism , Cell Line, Tumor , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Nude , Neoplasms/pathology , Oncogene Proteins, Fusion/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacokinetics , Sulfones/pharmacology , Xenograft Model Antitumor Assays
12.
Bioorg Med Chem Lett ; 26(7): 1720-5, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26923695

ABSTRACT

A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/enzymology , Cell Line, Tumor , Humans , Lung/drug effects , Lung/enzymology , Lung Neoplasms/enzymology , Male , Mice , Mice, SCID , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Naphthalenes/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/pharmacokinetics , Rats , Receptor Protein-Tyrosine Kinases/metabolism
13.
Arch Pharm Res ; 39(4): 453-464, 2016 04.
Article in English | MEDLINE | ID: mdl-26753914

ABSTRACT

A series of pyridazin-3-one substituted with morpholino-pyrimidine derivatives was synthesized and evaluated as tyrosine kinase inhibitors against c-Met enzyme, and anti-proliferative activities of Hs746T human gastric cancer cell line. Most of compounds exhibited good biological activity, while compound 10, 12a, 14a displayed excellent c-Met enzyme inhibitory activities and Hs746T cell-based activities.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Drug Discovery , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridazines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Pyridazines/chemical synthesis , Pyridazines/chemistry
14.
BMC Cancer ; 16: 35, 2016 Jan 22.
Article in English | MEDLINE | ID: mdl-26801760

ABSTRACT

BACKGROUND: c-Met signaling has been implicated in oncogenesis especially in cells with c-met gene amplification. Since 20 % of gastric cancer patients show high level of c-Met expression, c-Met has been identified as a good candidate for targeted therapy in gastric cancer. Herein, we report our newly synthesized c-Met inhibitor by showing its efficacy both in vitro and in vivo. METHODS: Compounds with both triazolopyrazine and pyridoxazine scaffolds were synthesized and tested using HTRF c-Met kinase assay. We performed cytotoxic assay, cellular phosphorylation assay, and cell cycle assay to investigate the cellular inhibitory mechanism of our compounds. We also conducted mouse xenograft assay to see efficacy in vivo. RESULTS: KRC-00509 and KRC-00715 were selected as excellent c-Met inhibitors through biochemical assay, and exhibited to be exclusively selective to c-Met by kinase panel assay. Cytotoxic assays using 18 gastric cancer cell lines showed our c-Met inhibitors suppressed specifically the growth of c-Met overexpressed cell lines, not that of c-Met low expressed cell lines, by inducing G1/S arrest. In c-met amplified cell lines, c-Met inhibitors reduced the downstream signals including Akt and Erk as well as c-Met activity. In vivo Hs746T xenograft assay showed KRC-00715 reduced the tumor size significantly. CONCLUSIONS: Our in vitro and in vivo data suggest KRC-00715 is a potent and highly selective c-Met inhibitor which may have therapeutic potential in gastric tumor with c-Met overexpression.


Subject(s)
Cell Proliferation/drug effects , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-met/biosynthesis , Pyrazines/administration & dosage , Stomach Neoplasms/drug therapy , Triazoles/administration & dosage , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-met/genetics , Pyrazines/chemical synthesis , Signal Transduction/drug effects , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Triazoles/chemical synthesis , Xenograft Model Antitumor Assays
15.
Bioorg Med Chem ; 24(2): 207-19, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26712094

ABSTRACT

Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Tetrahydroisoquinolines/pharmacology , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Female , Humans , Mice , Mice, Nude , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Tetrahydroisoquinolines/chemistry , Xenograft Model Antitumor Assays
16.
Eur J Med Chem ; 103: 210-22, 2015 Oct 20.
Article in English | MEDLINE | ID: mdl-26355532

ABSTRACT

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC50 values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Drug Resistance, Neoplasm/drug effects , Glioblastoma/drug therapy , Quinazolines/pharmacology , Urea/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioblastoma/pathology , Humans , Models, Molecular , Molecular Conformation , Quinazolines/chemistry , Structure-Activity Relationship , Temozolomide , Urea/analogs & derivatives , Urea/chemistry
17.
Bioorg Med Chem Lett ; 25(18): 3992-8, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26235945
18.
Biochem Biophys Res Commun ; 464(3): 762-7, 2015 Aug 28.
Article in English | MEDLINE | ID: mdl-26168728

ABSTRACT

Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151_L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15-20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Oncogene Proteins, Fusion/antagonists & inhibitors , Oncogene Proteins, Fusion/genetics , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Crizotinib , Female , Humans , Lung Neoplasms/genetics , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred BALB C , Mice, Nude , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/genetics , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Pyrazoles/pharmacology , Pyridines/pharmacology , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
19.
Acta Biomater ; 24: 279-285, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26102337

ABSTRACT

Drug delivery using thermosensitive liposomes (TSL) has significant potential for tumor drug targeting and can be combined with local hyperthermia to trigger drug release. Although TSL-mediated drug delivery can be effective by itself, we developed doxorubicin (DOX)-containing CO2 bubble-generating TSL (TSL-C) that were found to enhance the antitumor effects of DOX owing to the synergism between burst release of drug and hyperthermia-induced CO2 generation. An ultrasound imaging system was used to monitor hyperthermia-induced CO2 generation in TSL-C and the results revealed that hyperthermia-induced CO2 generation in TSL-C led to increased DOX release compared to that observed for non-CO2-generating TSL. Moreover, TSL-C significantly inhibited the tumor growth in MDA-MB-231 tumor-bearing mice compared to TSL (p<0.004). Taken together, we demonstrated that the TSL-C platform increased the therapeutic efficacy of cancer chemotherapy and showed the applicability of this approach to increase drug release within the tumor microenvironment. As a novel and highly effective drug delivery platform, TSL-C has great potential for use in a broad range of applications for the treatment of various human diseases. STATEMENT OF SIGNIFICANCE: We have developed a novel method for drug release from liposomes by gas (CO2) generation in tumor microenvironment. In addition, we demonstrate therapeutic efficacy in breast carcinoma. CO2-generated liposomal doxorubicin is a novel and highly attractive delivery system for anticancer drug with the potential for broad applications in human disease.


Subject(s)
Breast Neoplasms/drug therapy , Carbon Dioxide/chemistry , Doxorubicin/chemistry , Doxorubicin/pharmacology , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Liposomes , Mice , Mice, Nude , Xenograft Model Antitumor Assays
20.
Bioorg Med Chem Lett ; 24(21): 5093-7, 2014 11 01.
Article in English | MEDLINE | ID: mdl-25282552

ABSTRACT

We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine substituents.


Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridazines/chemistry , Binding Sites , Cell Line , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-met/metabolism , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...