Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia

• DOI: 10.1038/s41375-018-0364-x
• Publication Date: 2019-01-30T17:15:17Z
• Authors: Rong Chen; Mingzhao Zhu; Rajan R. Chaudhari; Omar Robles; Yuling Chen; Wesley Skillern; Qun Qin; William G. Wierda; Shuxing Zhang; Kenneth G. Hull; Daniel Romo; William Plunkett
• Keywords: Aged, 80 and over; Male; Models, Molecular; 0303 health sciences; Apoptosis; Drug Synergism; Middle Aged; Bridged Bicyclo Compounds, Heterocyclic; Prognosis; Leukemia, Lymphocytic, Chronic, B-Cell; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Eukaryotic Initiation Factor-4A; Biomarkers, Tumor; Epoxy Compounds; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Drug Therapy, Combination; Female; Macrolides; Aged; Follow-Up Studies

The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL.