'We believe this data sheds light on the capacity of Onconova's targeted anti-cancer agent rigosertib to modulate the RAS pathway,' said
The study compared the composition and activity of non-clinical grade rigosertib with clinical grade rigosertib that is approved for investigational use in humans. The authors found that non-clinical grade rigosertib used in in vitro studies by others contained impurities and degradation products in sufficient quantities to impact cellular function. In contrast, clinical grade rigosertib, which has been used in all clinical studies to-date, is free of this impurity. Using vincristine as a control, the ability of both compounds to bind tubulin (a mechanism of action seen in less targeted chemotherapy agents) was then measured. In vitro assay results indicated that both non-clinical grade rigosertib and the vincristine control showed tubulin binding activity, while clinical-grade rigosertib did not exhibit detectable tubulin-binding activity. Furthermore, cell lines expressing mutant beta-tubulin remained sensitive to rigosertib.
'We believe that the impurities found in non-clinical grade rigosertib, but not clinical-grade rigosertib, are responsible for the cellular effects observed such as tubulin disruption. Impurities are often found in non-clinical grade products and hence the reason these materials are not permitted in clinical trials,' said
'Rigosertib is a RAS mimetic that binds to RAS binding domains of RAS effectors and inhibits growth of tumor cells in pre-clinical models. Our studies showed that clinical grade rigosertib does not exhibit tubulin binding activity. Clinical studies conducted by
Rigosertib, Onconova's lead candidate, is a proprietary Phase 3 small molecule. A key publication in a preclinical model reported rigosertib's ability to block cellular signaling by targeting RAS effector pathways (Divakar, S.K., et al., 2016: 'A
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