Rigosertib is a small molecule that inhibits cellular signaling in cancer cells by acting as a Ras mimetic. This is believed to be mediated by the binding of rigosertib to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf (see video) and PI3K kinases.  In contrast to many kinase inhibitors, rigosertib does not interact at the ATP binding site, but acts via allosteric inhibition.  This mechanism of action exemplifies a new approach to block the interactions between Ras and its targets with RBD sites. Similarities in the tertiary structures of RBDs suggest that rigosertib may inhibit multiple Ras-driven signaling pathways.

Current clinical development of rigosertib is centered upon the therapeutic management of myelodysplastic syndromes (MDS), a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis that often develop into acute myeloid leukemia (AML).  The pathogenesis of MDS may be characterized by signaling through oncogenic Ras and Ras effector proteins.

Rigosertib, as an intravenous formulation, is in advanced clinical development for the treatment of higher-risk MDS. An oral formulation of rigosertib is being developed as a single agent for the treatment of lower-risk MDS and in combination with azacitidine for the treatment of MDS and AML.  To date, more than 500 MDS patients have been enrolled in clinical trials with rigosertib.