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• W3003907908 abstract "Summary We recently used CRISPRi/a-based chemical-genetic screens and targeted cell biological, biochemical, and structural assays to determine that rigosertib, an anti-cancer agent in phase III clinical trials, kills cancer cells by destabilizing microtubules. In a recent manuscript, Reddy and co-workers suggest that this microtubule-destabilizing activity of rigosertib is mediated not by rigosertib itself but by a contaminating degradation product of rigosertib, ON01500, present in formulations obtained from commercial vendors (Baker et al., 2019). Here, we demonstrate that treatment of cells with pharmaceutical-grade rigosertib (>99.9% purity) results in qualitatively indistinguishable phenotypes as treatment with commercially obtained rigosertib across multiple assays. The two compounds have indistinguishable chemical-genetic interactions with genes involved in modulating the microtubule network ( KIF2C and TACC3 ), both destabilize microtubules in cells and in vitro , and both show substantially reduced toxicity in cell lines expressing a rationally-designed mutant of tubulin (L240F TUBB mutant), in which the rigosertib binding site in tubulin is mutated. Importantly, the specificity of the L240F TUBB mutant for microtubule-destabilizing agents, which is disputed by Reddy and co-workers, was recently confirmed by an independent research group (Patterson et al., 2019). We conclude that rigosertib kills cancer cells by destabilizing microtubules, in agreement with our original findings." @default.
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• W3003907908 date "2020-01-29" @default.
• W3003907908 modified "2023-10-06" @default.
• W3003907908 title "Pharmaceutical-grade Rigosertib is a Microtubule-destabilizing Agent" @default.
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• W3003907908 doi "https://doi.org/10.1101/2020.01.28.923235" @default.
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