Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure–Activity Relationship, and Biological Activity

Abstract

Cyclin D proteins are elevated in many cancer cells and targeted deletion of Cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel non-enzymatic target for cancer therapeutics. We have developed novel, non-alkylating styryl benzyl sulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized Styryl Benzyl Sulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, non-alkylating (E) styryl benzyl sulfones, and the development of the novel anti-cancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}-acetate (ON 01910.Na), which is in Phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.

Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer

“…In vitro , rigosertib induces cytotoxicity against a broad range of human tumor-derived cell lines, with IC50s ranging from 50 to 250 nM (39, 46). Rigosertib treatment alone inhibits tumor growth in xenograft models (39, 46, 47).…”

“…Rigosertib treatment alone inhibits tumor growth in xenograft models (39, 46, 47). In fact, the addition of rigosertib improves the activity of oxaliplatin, doxorubicin, gemcitabine, paclitaxel, and vincristine.…”

“…Rigosertib is the sodium salt of (E)-2,4,6-trimethoxystyryl-3-carboxymethylamino-4-methoxybenzyl sulfone, a member of a broader class of unsaturated sulfone kinase inhibitors (20). Notably different from other kinase inhibitors, this class of molecules does not compete for the ATP-binding site of kinases but rather, allosterically inhibits substrate binding (Figure 1).…”

Phase I Study of Oral Rigosertib (ON 01910.Na), a Dual Inhibitor of the PI3K and Plk1 Pathways, in Adult Patients with Advanced Solid Malignancies

“…Rigosertib (Estybon; ON01910.Na) is a stryryl sulfone, ATP-independent, allosteric, multikinase inhibitor (18). Its complex mechanism of action involves indirect suppression of the PI3K and Plk1 pathways, likely resulting from rigosertib binding to c-Raf that, in turn, impairs c-Raf/coenzyme interactions (19–22).…”

Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies

“…1,2 As a class, styrylbenzylsulfones inhibit cell cycle progression and induce mitotic arrest of tumor cells with less toxicity to normal human cells. 3,4 ON 01910.Na (rigosertib) is a styryl sulfonyl compound that demonstrated inhibition of phosphatidylinositol-3-kinase (PI3K), preferentially targeting the PI3Kα and PI3Kβ isoforms, and triggered apoptosis via the release of cytochrome c from mitochondria in MCL cell lines.…”