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Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia.
- Source :
-
Leukemia [Leukemia] 2019 Jul; Vol. 33 (7), pp. 1663-1674. Date of Electronic Publication: 2019 Jan 30. - Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Aged
Aged, 80 and over
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Drug Synergism
Drug Therapy, Combination
Eukaryotic Initiation Factor-4A chemistry
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Leukemia, Lymphocytic, Chronic, B-Cell metabolism
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Male
Middle Aged
Models, Molecular
Myeloid Cell Leukemia Sequence 1 Protein genetics
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Prognosis
Protein Conformation
RNA, Messenger antagonists & inhibitors
RNA, Messenger genetics
RNA, Messenger metabolism
Tumor Cells, Cultured
Apoptosis drug effects
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Epoxy Compounds pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Macrolides pharmacology
Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors
Protein Biosynthesis drug effects
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Sulfonamides pharmacology
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 33
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 30700841
- Full Text :
- https://doi.org/10.1038/s41375-018-0364-x