Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)

• Published in: Pharmaceutics Vol. 15; no. 4; p. 1232
• Main Authors: Monfort-Vengut, Ana, de Cárcer, Guillermo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2023; MDPI
• Subjects: Analysis; Apoptosis; Binding sites; Biomarkers; Cancer; cancer therapy; Care and treatment; Cell cycle; Cell division; Cell growth; Clinical trials; Cytotoxicity; Drug targeting; Genotype & phenotype; kinase allosteric inhibition; Kinases; ON-01910.Na; Phosphorylation; Plk1; Ras; Review; rigosertib; Spain; cancer therapy; stress-signaling pathways; microtubule-destabilizing agents; Plk1; Ras; JNK; rigosertib; ON-01910.Na; kinase allosteric inhibition; PI3K/Akt
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics15041232

Rigosertib (ON-01910.Na) is a small-molecule member of the novel synthetic benzyl-styryl-sulfonate family. It is currently in phase III clinical trials for several myelodysplastic syndromes and leukemias and is therefore close to clinical translation. The clinical progress of rigosertib has been hampered by a lack of understanding of its mechanism of action, as it is currently considered a multi-target inhibitor. Rigosertib was first described as an inhibitor of the mitotic master regulator Polo-like kinase 1 (Plk1). However, in recent years, some studies have shown that rigosertib may also interact with the PI3K/Akt pathway, act as a Ras-Raf binding mimetic (altering the Ras signaling pathway), as a microtubule destabilizing agent, or as an activator of a stress-induced phospho-regulatory circuit that ultimately hyperphosphorylates and inactivates Ras signaling effectors. Understanding the mechanism of action of rigosertib has potential clinical implications worth exploring, as it may help to tailor cancer therapies and improve patient outcomes.