@article{237cfb52f8124beeb57c93f6ec6bc2d0,
title = "A Contaminant Impurity, Not Rigosertib, Is a Tubulin Binding Agent",
abstract = "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 β-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.",
keywords = "ON01500, ON01910, RAS, Ras binding domain, rigosertib, tubulin polymerization",
author = "Baker, {Stacey J.} and Cosenza, {Stephen C.} and Saikrishna Athuluri-Divakar and Reddy, {M. V.Ramana} and {Vasquez-Del Carpio}, Rodrigo and Rinku Jain and Aggarwal, {Aneel K.} and Reddy, {E. Premkumar}",
note = "Funding Information: We thank Dr. Jonathan Weissman for providing the lentiviral constructs encoding WT and L240F β-tubulin as well as lentiviruses encoding the same. This work was supported by grants from Onconova Therapeutics Inc. (Newtown, PA), the U.S. Army Medical Research and Materiel Command (LC160287), and the National Institutes of Health (NIH) (5R21CA227963-02) (to E.P.R.). Use of the flow cytometry shared resource facility was supported by a NIH Cancer Center support grant (P30CA196521 to the Tisch Cancer Institute). S.J.B. performed the tubulin polymerization assays, MST, cell-based assays, and flow cytometry studies. S.C.C. generated cell lines and performed cell-based assays. S.A.-D. and M.V.R.R. performed the tubulin polymerization assays and MST. R.V.-D.C. and R.J. performed the structural studies. A.K.A. and E.P.R. designed studies, analyzed data, and wrote the paper. E.P.R. is an equity holder, board member, and paid consultant of Onconova Therapeutics. S.J.B. is a paid consultant of Onconova Therapeutics. M.V.R.R. and S.C.C. are stockholders and paid consultants of Onconova Therapeutics, Inc. M.V.R.R. and E.P.R. are named inventors on pending and/or issued patents filed by Temple University. Funding Information: We thank Dr. Jonathan Weissman for providing the lentiviral constructs encoding WT and L240F β-tubulin as well as lentiviruses encoding the same. This work was supported by grants from Onconova Therapeutics Inc. (Newtown, PA), the U.S. Army Medical Research and Materiel Command ( LC160287 ), and the National Institutes of Health (NIH) ( 5R21CA227963-02 ) (to E.P.R.). Use of the flow cytometry shared resource facility was supported by a NIH Cancer Center support grant ( P30CA196521 to the Tisch Cancer Institute). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jul,
day = "2",
doi = "10.1016/j.molcel.2020.05.024",
language = "English",
volume = "79",
pages = "180--190.e4",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "1",
}