{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/86200"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/86200","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Developing 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 Kinases","abstract":"Poly-(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.","abstract_html":"Poly-(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.","abstract_has_math":false,"creators":["Sulier, Kiaya Minh-Li"],"institution":"Virginia Tech","degree_name":"Master of Science","degree_level":"masters","degree_discipline":"Chemistry","degree_department":"Chemistry","school":null,"contributors":[],"advisors":[],"committee_chairs":["Josan, Jatinder"],"committee_members":["Carlier, Paul R.","Merola, Joseph S.","Kingston, David G. I."],"year":2017,"date_issued":"2017-06-08","date_published":"2017-06-08","updated_at":"2026-07-22T22:19:29Z","subjects":["Poly-(ADP-Ribosyl) Polymerase (PARP)","cyclin-dependent kinase 1 (CDK1)","triple negative breast cancer (TNBC)","benzodiazepines","isoform specific inhibitors"],"languages":[],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:12148"],"render_values":[{"text":"vt_gsexam:12148","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10919/86200","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Josan, Jatinder"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Carlier, Paul R.","Merola, Joseph S.","Kingston, David G. 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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."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["The aim of this work is to explore the therapeutic potential of poly-(ADP-ribosyl) polymerase inhibitors (PARPi) for the treatment of ovarian and breast cancer, specifically triple negative breast cancer. Poly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. Currently, there are three FDA approved PARPi - olaparib, isoforms. Further, tumors have been shown to develop resistance to PARPi. Herein, we explored the 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-one scaffold as a potential PARP1/2-selective rucaparib, and niraparib; however, these PARPi demonstrate non-selectivity amongst the PARP inhibitor and its possibility for targeted pharmacology with other kinases."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Master of Science"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["Developing 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 Kinases"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Josan, Jatinder"],"dc:contributor.committeemember":["Carlier, Paul R.","Merola, Joseph S.","Kingston, David G. I."],"dc:contributor.department":["Chemistry"],"dc:creator":["Sulier, Kiaya Minh-Li"],"dc:date.accessioned":["2018-12-01T07:00:51Z"],"dc:date.available":["2018-12-01T07:00:51Z"],"dc:date.issued":["2017-06-08"],"dc:description.abstract":["Poly-(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."],"dc:description.abstractgeneral":["The aim of this work is to explore the therapeutic potential of poly-(ADP-ribosyl) polymerase inhibitors (PARPi) for the treatment of ovarian and breast cancer, specifically triple negative breast cancer. Poly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. Currently, there are three FDA approved PARPi - olaparib, isoforms. Further, tumors have been shown to develop resistance to PARPi. Herein, we explored the 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-one scaffold as a potential PARP1/2-selective rucaparib, and niraparib; however, these PARPi demonstrate non-selectivity amongst the PARP inhibitor and its possibility for targeted pharmacology with other kinases."],"dc:description.degree":["Master of Science"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:12148"],"dc:identifier.uri":["http://hdl.handle.net/10919/86200"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["Poly-(ADP-Ribosyl) Polymerase (PARP)","cyclin-dependent kinase 1 (CDK1)","triple negative breast cancer (TNBC)","benzodiazepines","isoform specific inhibitors"],"dc:title":["Developing 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 Kinases"],"dc:type":["Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["masters"],"thesis:degree_name":["Master of Science"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:19:29Z"}