Omacetaxine: a protein translation inhibitor for treatment of chronic myelogenous leukemia

Abstract

Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein, which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKI) have revolutionized how CML is treated. Although the majority of patients respond to these kinase inhibitors, a subset becomes resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently approved by the U.S. Food and Drug Administration for Philadelphia-positive CML either in the chronic or the accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m(2) twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in the chronic phase and major hematologic response in 27% of patients in the accelerated phase. Laboratory investigations unraveled the mechanism of action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life that makes it susceptible to protein translation inhibitors. Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminution of short-lived proteins, such as Bcr-Abl, followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.

Figure 1. Oncoprotein synthesis and mechanism of action of omacetaxine mepesuccinate

A. Oncogenes are transcribed to mRNAs followed by protein synthesis on ribosomes to produce oncoproteins such as Bcr-Abl, Mcl-1, Myc. B. Oncogenes are transcribed but protein synthesis on ribosomes is blocked by action of omacetaxine. This results in overall inhibition of protein synthesis. Proteins with short half-lives such as Bcr-Abl, Mcl-1, and Myc diminish. If cells are dependent on these proteins for survival, they undergo apoptosis.