The PIM-1 kinase is a serine/threonine kinase that has been implicated in the development of many human cancers, including leukemias, lymphomas, and prostate cancer. We have endeavored to identify and characterize a selective inhibitor of the PIM- 1 kinase. Such an inhibitor would have utility as a laboratory tool for the study of PIM-1 kinase function and as a template for the design of molecular therapeutics for diseases in which PIM-1 kinase activity is dysregulated.
Using phage display techniques we identified the peptide, HGVKKRPHNPYG, as a probable pseudosubstrate of the PIM-1 kinase with inhibitory activity in the low micromolar range in in vitro kinase assays. However, the peptide lacked sufficient potency for our objectives; hence we employed a second approach - the computational design of a novel PIM-1 kinase antagonist.
We created a homology model of the PIM-1 kinase that was subsequently determined to be structurally similar to a recently published crystal structure of the PIM-1 kinase. Docking studies using the PIM-1 kinase model demonstrated that the AFFINITY module of Insightll, under the parameters employed, was unable to accurately predict the potency of known PIM-1 kinase inhibitors. Consequently, we utilized comparative molecular field analysis, which resulted in a strong correlation of predicted IC50 vs. experimental IC50 values for known flavonoid inhibitors of the PIM-1 kinase. Thus we have created the first predictive model that may be used for the rational design of small molecule inhibitors of the PIM-1 kinase.
We have also performed an extensive screen of small molecules with structures similar to known kinase inhibitors and identified quercetagetin as a potent inhibitor of the PIM-1 kinase, with an in vitro IC50 of 0.34 pM. Lineweaver-burk analyses of the reaction kinetics demonstrated that quercetagetin is an ATP competitive inhibitor the PIM-1 kinase. We have also determined that quercetagetin is selective for the PIM-1 kinase over many other kinases and that quercetagetin successfully inhibits PIM-1 kinase activity in mammalian cells. Therefore quercetagetin may be an effective tool for the laboratory study of the PIM-1 kinase, and may serve as a template for the design of molecular therapeutics directed against the PIM-1 kinase.
","abstract_html":"<p>The PIM-1 kinase is a serine/threonine kinase that has been implicated in the development of many human cancers, including leukemias, lymphomas, and prostate cancer. We have endeavored to identify and characterize a selective inhibitor of the PIM- 1 kinase. Such an inhibitor would have utility as a laboratory tool for the study of PIM-1 kinase function and as a template for the design of molecular therapeutics for diseases in which PIM-1 kinase activity is dysregulated.</p> <p>Using phage display techniques we identified the peptide, HGVKKRPHNPYG, as a probable pseudosubstrate of the PIM-1 kinase with inhibitory activity in the low micromolar range in <em>in vitro</em> kinase assays. However, the peptide lacked sufficient potency for our objectives; hence we employed a second approach - the computational design of a novel PIM-1 kinase antagonist.</p> <p>We created a homology model of the PIM-1 kinase that was subsequently determined to be structurally similar to a recently published crystal structure of the PIM-1 kinase. Docking studies using the PIM-1 kinase model demonstrated that the AFFINITY module of Insightll, under the parameters employed, was unable to accurately predict the potency of known PIM-1 kinase inhibitors. Consequently, we utilized comparative molecular field analysis, which resulted in a strong correlation of predicted IC<sub>50 </sub>vs. experimental IC<sub>50</sub> values for known flavonoid inhibitors of the PIM-1 kinase. Thus we have created the first predictive model that may be used for the rational design of small molecule inhibitors of the PIM-1 kinase.</p> <p>We have also performed an extensive screen of small molecules with structures similar to known kinase inhibitors and identified quercetagetin as a potent inhibitor of the PIM-1 kinase, with an<em> in vitro</em> IC<sub>50</sub> of 0.34 pM. Lineweaver-burk analyses of the reaction kinetics demonstrated that quercetagetin is an ATP competitive inhibitor the PIM-1 kinase. We have also determined that quercetagetin is selective for the PIM-1 kinase over many other kinases and that quercetagetin successfully inhibits PIM-1 kinase activity in mammalian cells. Therefore quercetagetin may be an effective tool for the laboratory study of the PIM-1 kinase, and may serve as a template for the design of molecular therapeutics directed against the PIM-1 kinase.</p>","abstract_has_math":false,"creators":["Holder, Sheldon Levon"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Microbiology","degree_department":null,"school":null,"contributors":["Michael B. Lilly","Carlos Casiano","Penelope Duerken-Hughes","Mark Johnson","Jonathan Neidigh","Lawrence Sowers"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2005,"date_issued":"2005-09-01T07:00:00Z","date_published":"2005-09-01T07:00:00Z","updated_at":"2026-07-24T02:53:08Z","subjects":["Microbiology","Protein Kinases; Proto-Oncogene Proteins c-pim-1 -- antagonists and inhibitors; Neoplasms -- genetics."],"languages":["English"],"rights":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholarsrepository.llu.edu/etd/597","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Michael B. 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The author retains all other copyrights."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarsrepository.llu.edu/etd/597"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The PIM-1 kinase is a serine/threonine kinase that has been implicated in the development of many human cancers, including leukemias, lymphomas, and prostate cancer. We have endeavored to identify and characterize a selective inhibitor of the PIM- 1 kinase. Such an inhibitor would have utility as a laboratory tool for the study of PIM-1 kinase function and as a template for the design of molecular therapeutics for diseases in which PIM-1 kinase activity is dysregulated.
Using phage display techniques we identified the peptide, HGVKKRPHNPYG, as a probable pseudosubstrate of the PIM-1 kinase with inhibitory activity in the low micromolar range in in vitro kinase assays. However, the peptide lacked sufficient potency for our objectives; hence we employed a second approach - the computational design of a novel PIM-1 kinase antagonist.
We created a homology model of the PIM-1 kinase that was subsequently determined to be structurally similar to a recently published crystal structure of the PIM-1 kinase. Docking studies using the PIM-1 kinase model demonstrated that the AFFINITY module of Insightll, under the parameters employed, was unable to accurately predict the potency of known PIM-1 kinase inhibitors. Consequently, we utilized comparative molecular field analysis, which resulted in a strong correlation of predicted IC50 vs. experimental IC50 values for known flavonoid inhibitors of the PIM-1 kinase. Thus we have created the first predictive model that may be used for the rational design of small molecule inhibitors of the PIM-1 kinase.
We have also performed an extensive screen of small molecules with structures similar to known kinase inhibitors and identified quercetagetin as a potent inhibitor of the PIM-1 kinase, with an in vitro IC50 of 0.34 pM. Lineweaver-burk analyses of the reaction kinetics demonstrated that quercetagetin is an ATP competitive inhibitor the PIM-1 kinase. We have also determined that quercetagetin is selective for the PIM-1 kinase over many other kinases and that quercetagetin successfully inhibits PIM-1 kinase activity in mammalian cells. Therefore quercetagetin may be an effective tool for the laboratory study of the PIM-1 kinase, and may serve as a template for the design of molecular therapeutics directed against the PIM-1 kinase.
"]},{"key":"dc:title","label":"Title","values":["Identification and Characterization of a Selective Inhibitor of the PIM-1 Kinase"]}]}],"canonical_facts":{"dc:contributor":["Michael B. Lilly","Carlos Casiano","Penelope Duerken-Hughes","Mark Johnson","Jonathan Neidigh","Lawrence Sowers"],"dc:creator":["Holder, Sheldon Levon"],"dc:description.abstract":["The PIM-1 kinase is a serine/threonine kinase that has been implicated in the development of many human cancers, including leukemias, lymphomas, and prostate cancer. We have endeavored to identify and characterize a selective inhibitor of the PIM- 1 kinase. Such an inhibitor would have utility as a laboratory tool for the study of PIM-1 kinase function and as a template for the design of molecular therapeutics for diseases in which PIM-1 kinase activity is dysregulated.
Using phage display techniques we identified the peptide, HGVKKRPHNPYG, as a probable pseudosubstrate of the PIM-1 kinase with inhibitory activity in the low micromolar range in in vitro kinase assays. However, the peptide lacked sufficient potency for our objectives; hence we employed a second approach - the computational design of a novel PIM-1 kinase antagonist.
We created a homology model of the PIM-1 kinase that was subsequently determined to be structurally similar to a recently published crystal structure of the PIM-1 kinase. Docking studies using the PIM-1 kinase model demonstrated that the AFFINITY module of Insightll, under the parameters employed, was unable to accurately predict the potency of known PIM-1 kinase inhibitors. Consequently, we utilized comparative molecular field analysis, which resulted in a strong correlation of predicted IC50 vs. experimental IC50 values for known flavonoid inhibitors of the PIM-1 kinase. Thus we have created the first predictive model that may be used for the rational design of small molecule inhibitors of the PIM-1 kinase.
We have also performed an extensive screen of small molecules with structures similar to known kinase inhibitors and identified quercetagetin as a potent inhibitor of the PIM-1 kinase, with an in vitro IC50 of 0.34 pM. Lineweaver-burk analyses of the reaction kinetics demonstrated that quercetagetin is an ATP competitive inhibitor the PIM-1 kinase. We have also determined that quercetagetin is selective for the PIM-1 kinase over many other kinases and that quercetagetin successfully inhibits PIM-1 kinase activity in mammalian cells. Therefore quercetagetin may be an effective tool for the laboratory study of the PIM-1 kinase, and may serve as a template for the design of molecular therapeutics directed against the PIM-1 kinase.
"],"dc:identifier":["https://scholarsrepository.llu.edu/etd/597"],"dc:language":["English"],"dc:rights":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."],"dc:subject":["Microbiology","Protein Kinases; Proto-Oncogene Proteins c-pim-1 -- antagonists and inhibitors; Neoplasms -- genetics."],"dc:title":["Identification and Characterization of a Selective Inhibitor of the PIM-1 Kinase"],"thesis:degree_discipline":["Microbiology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T02:53:08Z"}