Unknown

Dataset Information

0

Pharmaceutical-Grade Rigosertib Is a Microtubule-Destabilizing Agent.


ABSTRACT: We recently used CRISPRi/a-based chemical-genetic screens and 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. Reddy and co-workers (Baker et al., 2020, this issue of Molecular Cell) suggest that a contaminating degradation product in commercial formulations of rigosertib is responsible for the microtubule-destabilizing activity. Here, we demonstrate that cells treated with pharmaceutical-grade rigosertib (>99.9% purity) or commercially obtained rigosertib have qualitatively indistinguishable phenotypes across multiple assays. The two formulations have indistinguishable chemical-genetic interactions with genes that modulate microtubule stability, both destabilize microtubules in cells and in vitro, and expression of a rationally designed tubulin mutant with a mutation in the rigosertib binding site (L240F TUBB) allows cells to proliferate in the presence of either formulation. Importantly, the specificity of the L240F TUBB mutant for microtubule-destabilizing agents has been confirmed independently. Thus, rigosertib kills cancer cells by destabilizing microtubules, in agreement with our original findings.

SUBMITTER: Jost M 

PROVIDER: S-EPMC7332992 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications


We recently used CRISPRi/a-based chemical-genetic screens and 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. Reddy and co-workers (Baker et al., 2020, this issue of Molecular Cell) suggest that a contaminating degradation product in commercial formulations of rigosertib is responsible for the microtubule-destabilizing activity. Here, we demonstrate that cells tr  ...[more]

Similar Datasets

| S-EPMC5640507 | biostudies-literature
| S-EPMC5010991 | biostudies-literature
| S-EPMC5579042 | biostudies-literature
| S-EPMC4255183 | biostudies-other
| S-EPMC6085345 | biostudies-literature
| S-EPMC4747374 | biostudies-literature
| S-EPMC5105934 | biostudies-literature
| S-EPMC7918738 | biostudies-literature
| S-EPMC65660 | biostudies-literature
| S-EPMC4816114 | biostudies-literature