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Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia
- Source :
- Leukemia
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 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 :
- Male
Models, Molecular
0301 basic medicine
Cancer Research
Protein Conformation
Chronic lymphocytic leukemia
Apoptosis
Context (language use)
Plasma protein binding
Article
03 medical and health sciences
0302 clinical medicine
hemic and lymphatic diseases
Biomarkers, Tumor
Tumor Cells, Cultured
medicine
Humans
Initiation factor
RNA, Messenger
Aged
Aged, 80 and over
Sulfonamides
Chemistry
Drug Synergism
Translation (biology)
Hematology
Middle Aged
Bridged Bicyclo Compounds, Heterocyclic
Prognosis
medicine.disease
Leukemia, Lymphocytic, Chronic, B-Cell
Gene Expression Regulation, Neoplastic
Thiazoles
Leukemia
030104 developmental biology
Proto-Oncogene Proteins c-bcl-2
Oncology
Protein Biosynthesis
030220 oncology & carcinogenesis
eIF4A
Eukaryotic Initiation Factor-4A
Cancer research
Epoxy Compounds
Myeloid Cell Leukemia Sequence 1 Protein
Drug Therapy, Combination
Female
Macrolides
Follow-Up Studies
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....d4bb0ce90f3f51c1204a872922d90705