title: Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death.
abstract: 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 though 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.
authors.affiliation: University of Pittsburgh School of Medicine, Department of Computational & Systems Biology, HillmanCancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mustata
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Nicki
authors.initials: N
authors.lastname: Zevola
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bakan
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Epperly
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002474:Cell-Free System / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D016208:Databases, Factual; D015195:Drug Design; D005854:Germ Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000737:chemistry* / Q000494:pharmacology*; D014162:Transfection; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011837:Radiation-Protective Agents; D051020:bcl-X Protein