scholarly journals A Small-Molecule Inhibitor of RAD51 Reduces Homologous Recombination and Sensitizes Multiple Myeloma Cells to Doxorubicin

2014 ◽  
Vol 4 ◽  
Author(s):  
David A. Alagpulinsa ◽  
Srinivas Ayyadevara ◽  
Robert Joseph Shmookler Reis
Keyword(s):  
Multiple Myeloma ◽  
Homologous Recombination ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Myeloma Cells ◽  
Molecule Inhibitor

scholarly journals A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

Cancer Cell ◽  
2012 ◽  
Vol 22 (3) ◽  
pp. 345-358 ◽  
Author(s):  
Dharminder Chauhan ◽  
Ze Tian ◽  
Benjamin Nicholson ◽  
K.G. Suresh Kumar ◽  
Bin Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Myeloma Cells ◽  
Molecule Inhibitor ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Mi-63, a Small Molecule Inhibitor of MDM2-p53 Interaction, Has Significant In Vitro Activity in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3464-3464
Author(s):  
Shaji Kumar ◽  
Michael Timm ◽  
Michael P. Kline ◽  
Jessica L. Haug ◽  
Teresa K. Kimlinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Small Molecule ◽  
Myeloma Cell ◽  
Small Molecule Inhibitor ◽  
Wild Type ◽  
Myeloma Cells ◽  
Molecule Inhibitor

Abstract Background: Multiple myeloma (MM) is a plasma cell proliferative disorder that results in considerable morbidity and mortality. As it is incurable with the current therapeutic approaches, more effective therapies based on better understanding of the pathobiology of the disease are needed. In MM, malignant plasma cells are characterized by low proliferative and apoptotic rates compared to other malignancies. The tumor suppressor gene p53, responsible for induction of cellular apoptosis in response to genotoxic stimuli, is relatively intact in most cases of myeloma. However, p53 mutations or deletion can occur late in the course of disease. Here we evaluate a novel small molecule inhibitor of the interaction between p53 and its negative regulator, MDM2, in the setting of myeloma. Methods and Results: Mi-63 was cytotoxic to several different myeloma cell lines with a median effect observed at approximately 2.5 μM in cell lines including MM1.S that express wild type p53 and between 10–15 μM in cells with mutated p53 as measured using an MTT cell viability assay. Additionally, Mi63 induced cytotoxicity in myeloma cell lines resistant to conventional agents such as Melphalan (LR50), Doxorubicin (Dox40) and Dexamethasone (MM1.R), indicating non-overlapping mechanisms. To evaluate the ability of the drug to induce cell death in the tumor microenvironment, MM cells were co-cultured with marrow stromal cells or in the presence of VEGF or IL-6, two cytokines known to be important for myeloma growth and survival. Mi63 was cytotoxic to myeloma cells under these conditions as well, at doses similar to those seen with myeloma cells alone. Mi63 was able to inhibit proliferation and induce apoptosis in myeloma cells in a dose- and time-dependent fashion, as demonstrated by flow cytometry using Annexin/PI staining as well as cell cycle studies. Treatment of myeloma cells with Mi63 was associated with early mitochondrial membrane depolarization, inversion of Bax/Bcl-2 ratio, and down regulation of Mcl-1, indicating induction of mitochondrial mechanisms of cell death. Mi63 was also cytotoxic to freshly isolated primary patient myeloma cells, inducing apoptosis in a dose-dependent manner. In the patient cells the drug appears to have a differential effect on the CD45 positive and negative cells. Conclusion: Mi-63 has significant activity in vitro in the setting of myeloma as demonstrated by its effect on myeloma cell lines and primary patient cells. It clearly induces apoptosis in myeloma cells, with higher activity seen in cells with wild type p53. Given the lack of p53 abnormalities in most of the patients with myeloma, this drug alone or in combination is likely to have significant clinical activity. Studies combining this with various DNA damaging drugs are in progress. These studies will eventually form the framework for future clinical studies.

scholarly journals TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma

Oncotarget ◽  
2018 ◽  
Vol 9 (26) ◽  
pp. 18480-18493 ◽  
Author(s):  
Kazuhide Nakayama ◽  
Magdalena M. Szewczyk ◽  
Carlo dela Sena ◽  
Hong Wu ◽  
Aiping Dong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

Blood ◽  
2014 ◽  
Vol 123 (5) ◽  
pp. 706-716 ◽  
Author(s):  
Ze Tian ◽  
Padraig D’Arcy ◽  
Xin Wang ◽  
Arghya Ray ◽  
Yu-Tzu Tai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Key Points

Key Points Deubiquitylating enzymes USP14 and UCHL5 are involved in the tumorigenesis of MM. b-AP15 is a specific USP14 and UCHL5 inhibitor, which blocks growth and induces apoptosis in MM cells.

scholarly journals A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

2019 ◽  
Vol 80 (3) ◽  
pp. 536-548 ◽  
Author(s):  
Yingcong Wang ◽  
Jing Huang ◽  
Bo Li ◽  
Han Xue ◽  
Guido Tricot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines

2013 ◽  
Vol 6 (1) ◽  
pp. 92 ◽  
Author(s):  
Cornel Phillip ◽  
Shadia Zaman ◽  
Shujun Shentu ◽  
Kumudha Balakrishnan ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Myeloma Cells ◽  
Molecule Inhibitor
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