Development of Small-Molecule PUMA Inhibitors for Mitigating Radiation-Induced Cell Death
| Autor: | Gabriela Mustata, Ahmet Bakan, Mei Li, Michael W. Epperly, Ivet Bahar, Lin Zhang, Joel S. Greenberger, Nicki Zevola, Jian Yu |
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| Rok vydání: | 2011 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Models Molecular Programmed cell death Databases Factual In silico Molecular Sequence Data bcl-X Protein Apoptosis Radiation-Protective Agents Plasma protein binding Molecular Dynamics Simulation Biology Transfection Article Mice Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases Puma Drug Discovery Animals Humans Protein Interaction Domains and Motifs p53 upregulated modulator of apoptosis Amino Acid Sequence Cell-Free System Molecular Structure General Medicine Lymphoid Progenitor Cells HCT116 Cells biology.organism_classification Molecular biology Small molecule Cell biology Germ Cells Proto-Oncogene Proteins c-bcl-2 Drug Design biology.protein Myeloid Cell Leukemia Sequence 1 Protein biological phenomena cell phenomena and immunity Pharmacophore Apoptosis Regulatory Proteins Protein Binding |
| Zdroj: | Current Topics in Medicinal Chemistry. 11:281-290 |
| ISSN: | 1568-0266 |
| Popis: | PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli. PUMA is particularly important in initiating radiation-induced apoptosis and damage in the gastrointestinal and hematopoietic systems. Unlike most BH3-only proteins, PUMA neutralizes all five known antiapoptotic Bcl-2 members through high affinity interactions with its BH3 domain to initiate mitochondria-dependent cell death. Using structural data on the conserved interactions of PUMA with Bcl-2-like proteins, we developed a pharmacophore model that mimics these interactions. In silico screening of the ZINC 8.0 database with this pharmacophore model yielded 142 compounds that could potentially disrupt these interactions. Thirteen structurally diverse compounds with favorable in silico ADME/Toxicity profiles have been retrieved from this set. Extensive testing of these compounds using cell-based and cell-free systems identified lead compounds that confer considerable protection against PUMA-dependent and radiation-induced apoptosis, and inhibit the interaction between PUMA and Bcl-xL. |
| Databáze: | OpenAIRE |
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