A Contaminant Impurity, Not Rigosertib, Is a Tubulin Binding Agent

被引：14

作者：

Baker, Stacey J. ^{[1
]}

Cosenza, Stephen C. ^{[1
]}

Athuluri-Divakar, Saikrishna ^{[1
,3
]}

Reddy, M. V. Ramana ^{[1
]}

Vasquez-Del Carpio, Rodrigo ^{[1
,4
]}

Jain, Rinku ^{[2
]}

Aggarwal, Aneel K. ^{[2
]}

Reddy, E. Premkumar ^{[1
,2
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Oncol Sci, One Gustave L Levy Pl,Box 1130, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, One Gustave L Levy Pl,Box 1215, New York, NY 10029 USA

[3] Univ Texas Southwestern Med Ctr, Dept Internal Med, Div Digest & Liver Dis, Simmons Comprehens Canc Ctr,Liver Tumor Translat, Dallas, TX 75390 USA

[4] Sandoz, 5200 Blue Lagoon Dr, Miami, FL 33126 USA

来源：

MOLECULAR CELL | 2020年 / 79卷 / 01期

基金：

美国国家卫生研究院;

关键词：

INHIBITOR RIGOSERTIB;

D O I：

10.1016/j.molcel.2020.05.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Rigosertib is a styryl benzyl sulfone that inhibits growth of tumor cells and acts as a RAS mimetic by binding to Ras binding domains of RAS effectors. A recent study attributed rigosertib's mechanism of action to microtubule binding. In that study, rigosertib was obtained from a commercial vendor. We compared the purity of clinical-grade and commercially sourced rigosertib and found that commercially sourced rigosertib contains approximately 5% ON01500, a potent inhibitor of tubulin polymerization. Clinical-grade rigosertib, which is free of this impurity, does not exhibit tubulin-binding activity. Cell lines expressing mutant b-tubulin have also been reported to be resistant to rigosertib. However, our study showed that these cells failed to proliferate in the presence of rigosertib at concentrations that are lethal to wild-type cells. Rigosertib induced a senescence-like phenotype in the small percentage of surviving cells, which could be incorrectly scored as resistant using short-term cultures.

引用

页码：180 / +

页数：15

共 13 条

[1] Rigosertib Is a More Effective Radiosensitizer Than Cisplatin in Concurrent Chemoradiation Treatment of Cervical Carcinoma, In Vitro and In Vivo [J].

Agoni, Lorenzo ;

Basu, Indranil ;

Gupta, Seema ;

Alfieri, Alan ;

Gambino, Angela ;

Goldberg, Gary L. ;

Reddy, E. Premkumar ;

Guha, Chandan .

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2014, 88 (05) :1180-1187

[2] A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling [J].

Athuluri-Divakar, Sai Krishna ;

Vasquez-Del Carpio, Rodrigo ;

Dutta, Kaushik ;

Baker, Stacey J. ;

Cosenza, Stephen C. ;

Basu, Indranil ;

Gupta, Yogesh K. ;

Reddy, M. V. Ramana ;

Ueno, Lynn ;

Hart, Jonathan R. ;

Vogt, Peter K. ;

Mulholland, David ;

Guha, Chandan ;

Aggarwal, Aneel K. ;

Reddy, E. Premkumar .

CELL, 2016, 165 (03) :643-655

[3] Plk1 Inhibition Causes Post-Mitotic DNA Damage and Senescence in a Range of Human Tumor Cell Lines [J].

Driscoll, Denise L. ;

Chakravarty, Arijit ;

Bowman, Doug ;

Shinde, Vaishali ;

Lasky, Kerri ;

Shi, Judy ;

Vos, Tricia ;

Stringer, Bradley ;

Amidon, Ben ;

D'Amore, Natalie ;

Hyer, Marc L. .

PLOS ONE, 2014, 9 (11)

[4] Evaluation of the novel mitotic modulator ON 01910.Na in pancreatic cancer and preclinical development of an ex vivo predictive assay [J].

Jimeno, A. ;

Chan, A. ;

Cusatis, G. ;

Zhang, X. ;

Wheelhouse, J. ;

Solomon, A. ;

Chan, F. ;

Zhao, M. ;

Cosenza, S. C. ;

Reddy, M. V. Ramana ;

Rudek, M. A. ;

Kulesza, P. ;

Donehower, R. C. ;

Reddy, E. P. ;

Hidalgo, M. .

ONCOGENE, 2009, 28 (04) :610-618

[5] Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent [J].

Jost, Marco ;

Chen, Yuwen ;

Gilbert, Luke A. ;

Horlbeck, Max A. ;

Krenning, Lenno ;

Menchon, Gregory ;

Rai, Ankit ;

Cho, Min Y. ;

Stern, Jacob J. ;

Prota, Andrea E. ;

Kampmann, Martin ;

Akhmanova, Anna ;

Steinmetz, Michel O. ;

Tanenbaum, Marvin E. ;

Weissman, Jonathan S. .

MOLECULAR CELL, 2017, 68 (01) :210-+

[6] An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site [J].

Lu, Yan ;

Chen, Jianjun ;

Xiao, Min ;

Li, Wei ;

Miller, Duane D. .

PHARMACEUTICAL RESEARCH, 2012, 29 (11) :2943-2971

[7] Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with abelson tyrosine kinase inhibitors, against break point cluster region-c-abelson-positive leukemia cells [J].

Okabe, Seiichi ;

Tauchi, Tetsuzo ;

Tanaka, Yuko ;

Sakuta, Juri ;

Ohyashiki, Kazuma .

ONCOTARGET, 2015, 6 (24) :20231-20240

[8] Determination of Degradation Kinetics and Effect of Anion Exchange Resin on Dissolution of Novel Anticancer Drug Rigosertib in Acidic Conditions [J].

Patel, Hardikkumar H. ;

Maniar, Manoj ;

Ren, Chen ;

Dave, Rutesh H. .

AAPS PHARMSCITECH, 2018, 19 (01) :93-100

[9] Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure-Activity Relationship, and Biological Activity [J].

Reddy, M. V. Ramana ;

Venkatapuram, Padmavathi ;

Mallireddigari, Muralidhar R. ;

Pallela, Venkat R. ;

Cosenza, Stephen C. ;

Robell, Kimberly A. ;

Akula, Balaiah ;

Hoffman, Benjamin S. ;

Reddy, E. Premkumar .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (18) :6254-6276

[10] Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy [J].

Silverman, Lewis R. ;

Greenberg, Peter ;

Raza, Azra ;

Olnes, Matthew J. ;

Holland, James F. ;

Reddy, Premkumar ;

Maniar, Manoj ;

Wilhelm, Francois .

HEMATOLOGICAL ONCOLOGY, 2015, 33 (02) :57-66

← 1 2 →