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.

LLU Discipline





Graduate School

First Advisor

Michael B. Lilly

Second Advisor

Carlos Casiano

Third Advisor

Penelope Duerken-Hughes

Fourth Advisor

Mark Johnson

Fifth Advisor

Jonathan Neidigh

Sixth Advisor

Lawrence Sowers

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Protein Kinases; Proto-Oncogene Proteins c-pim-1 -- antagonists and inhibitors; Neoplasms -- genetics.



Page Count

xv; 132

Digital Format


Digital Publisher

Loma Linda University Libraries

Usage 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.


Loma Linda University Electronic Theses and Dissertations

Collection Website



Loma Linda University. Del E. Webb Memorial Library. University Archives

Included in

Microbiology Commons