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dc.contributor.authorSulier, Kiaya Minh-Lien_US
dc.date.accessioned2018-12-01T07:00:51Z
dc.date.available2018-12-01T07:00:51Z
dc.date.issued2017-06-08en_US
dc.identifier.othervt_gsexam:12148en_US
dc.identifier.urihttp://hdl.handle.net/10919/86200
dc.description.abstractPoly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. PARP inhibitors (PARPi) have shown success in clinical trials for the treatment of homologous recombination-deficient cancers. Though proven effective initially, tumors treated with PARPi eventually develop resistance. Combinatorial therapeutics targeting PARP and other pathways that may re-sensitize tumors to PARP inhibition, including PI3K/AKT/mTor pathway, and cell-cycle checkpoints (such as CDKs, CHK, and Wee) are being tested. In this context, the synthetic lethality of cyclin-dependent kinase 1 (CDK1) and PARP1 is known. Evaluation of PARP1 and CDK1 pharmacophores led to the development of the tetrahydro-arylazepinone (TAAP) scaffold as a potential dual PARP1/CDK1 inhibitor. We screened a handful of TAAP analogs against PARP1 in a cell-free assay that identified the low micromolar PARP1 inhibitor 1,2,3,4-tetrahydro-5H-benzo[e][1,4]-diazepin-5-one (TBAP), which served as the lead compound. The analogous 1,2,3,4-tetrahydro-5H-pyrido[2,3-e][1,4]-diazepin-5-one (TPAP) series showed a similar bioactivity profile. Satisfyingly, the N1-benzyl TPAP analogue showed activity in the low nanomolar range. The TAAP series (i.e., 6/7-membered scaffold) unfortunately lacked CDK1 inhibitory activity. Finally, many PARPi's show poor isoform-selectivity. The development of isoform-selective PARPi can clarify the specific function of each PARP isoform and may reduce the adverse side effects shown by PARPi. A handful of TAAP analogs were screened against 13 PARP isoforms, where some compounds demonstrated exquisite PARP1/2 selectivity. Concurrently, we discovered an inhibitor for PARP11, an isoform that lacks any known synthetic ligand. Future directions are suggested towards fine-tuning the structure-activity relationship of TAAP-isoform selective PARPi as well as developing a dual PARP1/CDK1 inhibitor.en_US
dc.format.mediumETDen_US
dc.publisherVirginia Techen_US
dc.rightsThis item is protected by copyright and/or related rights. Some uses of this item may be deemed fair and permitted by law even without permission from the rights holder(s), or the rights holder(s) may have licensed the work for use under certain conditions. For other uses you need to obtain permission from the rights holder(s).en_US
dc.subjectPoly-(ADP-Ribosyl) Polymerase (PARP)en_US
dc.subjectcyclin-dependent kinase 1 (CDK1)en_US
dc.subjecttriple negative breast cancer (TNBC)en_US
dc.subjectbenzodiazepinesen_US
dc.subjectisoform specific inhibitorsen_US
dc.titleDeveloping 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinasesen_US
dc.typeThesisen_US
dc.contributor.departmentChemistryen_US
dc.description.degreeMaster of Scienceen_US
thesis.degree.nameMaster of Scienceen_US
thesis.degree.levelmastersen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineChemistryen_US
dc.contributor.committeechairJosan, Jatinderen_US
dc.contributor.committeememberCarlier, Paul R.en_US
dc.contributor.committeememberMerola, Joseph S.en_US
dc.contributor.committeememberKingston, David G.en_US


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