Iwamoto R.,Osaka University |
Mine N.,Osaka University |
Mine N.,CanBas Co. |
Mizushima H.,Osaka University |
Mekada E.,Osaka University
Journal of Cell Science | Year: 2017
Heparin-binding EGF-like growth factor (HB-EGF) plays an indispensable role in suppression of cell proliferation during mouse valvulogenesis. However, ligands of the EGF receptor (EGFR/ErbB1), including HB-EGF, are generally considered as growth-promoting factors, as shown in cancers. HB-EGF binds to and activates ErbB1 and ErbB4. We investigated the role of ErbB receptors in valvulogenesis in vivo using ErbB1- and ErbB4-deficient mice, and an ex vivo model of endocardial cushion explants.We show that HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4, and an ErbB1 ligand (or ligands) promotes cell proliferation through a homodimer of ErbB1.Moreover, a rescue experiment with cleavable or uncleavable isoforms of ErbB4 in ERBB4-null cells indicates that the cleavable JM-A, but not the uncleavable JM-B, splice variant ofErbB4 rescues the defect of the null cells. These data suggest that the cytoplasmic intracellular domain of ErbB4, rather than the membrane-anchored tyrosine kinase, achieves this suppression. Our study demonstrates that opposing signals generated by different ErbB dimer combinations function in the same cardiac cushion mesenchymal cells for proper cardiac valve formation. © 2017. Published by The Company of Biologists Ltd.
CanBas Co. | Date: 2016-10-21
This invention provides compounds including peptides and peptidomimetics that can be used to treat cell proliferative disorders, such as those associated with benign and malignant tumor cells, and combinations of T cell activating agents and/or an immune checkpoint inhibitors with and without peptides and peptidomimetics. The invention compounds and combinations can be used to inhibit cell growth, such as treat a tumor or cancer.
News Article | November 29, 2016
The report provides comprehensive information on the therapeutics under development for Malignant Pleural Mesothelioma, complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report provides an overview of key players involved in therapeutic development for Malignant Pleural Mesothelioma and features dormant and discontinued projects. The report helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. Complete report on Malignant Pleural Mesothelioma - Pipeline Review, H2 2016 addition with 55 market data tables and 15 figures, spread across 315 pages is available at http://www.reportsnreports.com/reports/764553-malignant-pleural-mesothelioma-pipeline-review-h2-2016.html This report features investigational drugs from across globe covering over 20 therapy areas and nearly 3,000 indications. The report is built using data and information sourced from Global Markets Directs proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, Investor presentations and featured press releases from company/university sites and industry-specific third party sources. Drug profiles featured in the report undergoes periodic review following a stringent set of processes to ensure that all the profiles are updated with the latest set of information. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis Advantagene, Inc.,Amphera BV,AnGes MG, Inc.,ArQule, Inc.,Bayer AG,Biogen Inc,Bionomics Limited,Biotecnol Limited,Boehringer Ingelheim GmbH,Boston Biomedical, Inc.,Bristol-Myers Squibb Company,CanBas Co., Ltd.,Concordia International Corp,Eli Lilly and Company,EnGeneIC Ltd,F. Hoffmann-La Roche Ltd.,Genelux Corporation,GlaxoSmithKline Plc,Juno Therapeutics Inc.,MedImmune LLC,Merck & Co., Inc. Inquire before buying http://www.reportsnreports.com/contacts/inquirybeforebuy.aspx?name=764553 premium report price at US$2000 for a single user PDF license).
Sakakibara K.,CanBas Co Ltd |
Saito N.,CanBas Co Ltd |
Sato T.,CanBas Co Ltd |
Suzuki A.,CanBas Co Ltd |
And 6 more authors.
Blood | Year: 2011
CRM1 plays an important role in the nuclear export of cargo proteins bearing nuclear exporting signal sequences. Leptomycin B (LMB), a well-known CRM1 inhibitor, possesses strong antitumor properties. However, its toxicity prevents it from being clinically useful. In this study, we demonstrate that a novel compound, CBS9106, inhibits CRM1- dependent nuclear export, causing arrest of the cell cycle and inducing apoptosis in a time- and dose-dependent manner for a broad spectrum of cancer cells, including multiple myeloma cells. CBS9106 reduces CRM1 protein levels significantly without affecting CRM1 mRNA expression. This effect could be reversed by adding bortezomib or LMB. Moreover, CBS9106-biotin allows capture of CRM1 protein by streptavidin beads in a competitive manner with LMB and vice versa. Mass spectrometric analysis shows that CBS9106 reacts with a synthetic CRM1 peptide that contains Cys528 but not with a Cys528 mutant peptide. Oral administration of CBS9106 significantly suppresses tumor growth and prolongs survival in mice bearing tumor xenograft without a significant loss in body weight.Areduced level of CRM1 protein is also observed in tumor xenografts isolated from mice treated with CBS9106. Taken together, these results indicate that CBS9106 is a novel reversible CRM1 inhibitor and a promising clinical candidate. © 2011 by The American Society of Hematology.
Mine N.,CanBas Co. |
Yamamoto S.,CanBas Co. |
Saito N.,CanBas Co. |
Yamazaki S.,CanBas Co. |
And 5 more authors.
Molecular Cancer Therapeutics | Year: 2011
CBP501 is an anticancer drug currently in randomized phase II clinical trials for patients with non-small cell lung cancer and malignant pleural mesothelioma. CBP501 was originally described as a unique G 2 checkpoint- directed agent that binds to 14-3-3, inhibiting the actions of Chk1, Chk2, mitogen-activated protein kinase-activated protein kinase 2, and C-Tak1. However, unlike a G 2 checkpoint inhibitor, CBP501 clearly enhances the accumulation of tumor cells at G 2-M phase that is induced by cisplatin or bleomycin at low doses and short exposure. By contrast, CBP501 does not similarly affect the accumulation of tumor cells at G 2-M that is induced by radiation, doxorubicin, or 5-fluorouracil treatment. Our recent findings point to an additional mechanism of action for CBP501. The enhanced accumulation of tumor cells at G 2-M upon combined treatment with cisplatin and CBP501 results from an increase in intracellular platinum concentrations, which leads to increased binding of platinum to DNA. The observed CBP501-enhanced platinum accumulation is negated in the presence of excess Ca 2+. Some calmodulin inhibitors behave similarly to, although less potently than, CBP501. Furthermore, analysis by surface plasmon resonance reveals a direct, high-affinity molecular interaction between CBP501 and CaM (K d = 4.62 × 10 -8 mol/L) that is reversed by Ca 2+, whereas the K d for the complex between CBP501 and 14-3-3 is approximately 10-fold weaker and is Ca 2+ independent. We conclude that CaM inhibition contributes to CBP5010s activity in sensitizing cancer cells to cisplatin or bleomycin. This article presents an additional mechanism of action which might explain the clinical activity of the CBP501-cisplatin combination. ©2011 AACR.
Saito N.,CanBas Co. |
Sakakibara K.,CanBas Co. |
Sato T.,CanBas Co. |
Friedman J.M.,CanBas Co. |
And 3 more authors.
Molecular Cancer Therapeutics | Year: 2014
Chromosome region maintenance 1 (CRM1) mediates the nuclear export of proteins and mRNAs, and is overexpressed in various cancers. Recent studies have also reported that CRM1 protein expression is a negative prognostic factor in patients with cancer. Therefore, CRM1 is considered a potential target for anticancer therapy. Our previous study demonstrated that CBS9106, a synthetic small-molecular inhibitor of CRM1, decreases CRM1 protein through proteasomal degradation without affecting CRM1 mRNA levels. However, the mechanism by which CRM1 is degraded is not well understood. Here, we demonstrate a novel signaling pathway that plays an important role in CBS9106-induced CRM1 degradation. We found that MLN4924, a selective inhibitor of NEDD8-activating enzyme (NAE), effectively inhibits cullin neddylation and attenuates CBS9106-induced CRM1 degradation in a time- and dose-dependent manner. MLN4924 also attenuated CBS9106-induced nuclear accumulation of Ran-binding protein 1 (RanBP1), cell growth inhibition, and apoptosis. Furthermore, RNAi-mediated knockdown of neddylation pathway proteins (NEDD8 and UBA3) or cullin ring ligase (CRL) component protein (Rbx1) attenuated CRM1 protein degradation and G1 phase cell-cycle arrest by CBS9106. Knockdown of CSN5 or CAND1 also partially inhibited CBS9106-induced CRM1 degradation. These findings demonstrate that CBS9106-induced CRM1 degradation is conferred by CRL activity involving the neddylation pathway, and that this response to CBS9106 leads to cell growth inhibition and apoptosis. ©2014 AACR.
CanBas Co. | Date: 2014-06-24
This invention provides compounds including peptides and peptidomimetics that can be used to treat cell proliferative disorders, such as those associated with benign and malignant tumor cells. While the invention is not limited to any particular mechanism, the compounds of the invention appear to function at least in part by inhibiting G2 cell cycle checkpoint. Thus, invention compounds can be used to inhibit cell growth alone or be used in combination with a nucleic acid damaging treatment to inhibit cell growth.
CanBas Co. | Date: 2010-11-19
Novel substituted azole diones are provided that kill cells, suppress cell proliferation, suppress cell growth, abrogate the cell cycle G2 checkpoint and/or cause adaptation to G2 cell cycle arrest. Methods of making and using the invention compounds are provided. The invention provides substituted azole diones to treat cell proliferation disorders. The invention includes the use of substituted azole diones to selectively kill or suppress cancer cells without additional anti-cancer treatment. The invention includes the use of cell cycle G2-checkpoint-abrogating substituted azole diones to selectively sensitize cancer cells to DNA damaging reagents, treatments and/or other types of anti-cancer reagents.
CanBas Co. | Date: 2015-05-21
Disclosed herein, inter alia, are methods and uses for treating a cancer in a subject. In various embodiments, a method or use includes measuring expression of nuclear factor erythroid-2 related factor 2 (NRF2), or an NRF2 target gene, in a candidate subject having cancer, or a cancer sample from the candidate subject, and determining the amount of NRF2 in the sample or in the subject having cancer, then comparing the amount of NRF2 determined, or NRF2 target gene determined, to a baseline or reference amount of NRF2 or NRF2 target gene. If the amount of NRF2 or NRF2 target gene in the sample or in the subject having cancer is less than the baseline or reference amount of NRF2 or NRF2 target gene, the subject having the cancer may be or is treated with a peptide or peptidomimetic sequence set forth herein, such as P1, P2, P3, P4, P5, P6 (SEQ ID NO:1) or P6, P5, P4, P3, P2, P1 (SEQ ID NO:2), e.g., CBP501.
CanBas Co. | Date: 2016-11-02
Substituted azole diones (II) and (III) are provided that kill cells, suppress cell proliferation, suppress cell growth, abrogate the cell cycle G2 checkpoint and/or cause adaptation to G2 cell cycle arrest. Methods of making the invention compounds are provided. The invention provides substituted azole diones (II) and (III) to treat cell proliferation disorders. The invention includes the substituted azole diones (II) and (III) for use to selectively kill or suppress cancer cells without additional anti-cancer treatment. The invention includes the cell cycle G2- checkpoint-abrogating substituted azole diones (II) and (III) for use to selectively sensitize cancer cells to DNA damaging reagents, treatments and/or other types of anti-cancer reagents.