Graduation Date

Fall 12-15-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Amarnath Natarajan

Second Advisor

Keith Johnson

Third Advisor

Xu Luo

Abstract

The apoptotic pathway involves a tightly regulated network of proteins which respond to various stimuli. Previous studies have indicated Mcl-1 and Bcl-xL are intimately involved in determining cell fate, and if both are concurrently neutralized, it activates the apoptotic pathway. The inactivation of Bcl-xL and Mcl-1 as a mechanism to trigger the intrinsic apoptotic response can be used as a platform to develop therapeutic strategies to target cancer cells. The apoptotic pathway is largely dysregulated and often leads to therapy resistance in cancer cells. Although direct inhibitors of Bcl-xL have been developed and have advanced to clinical trials, development of direct Mcl-1 inhibitors have been elusive. Therefore, we aim to develop small molecule inhibitors (SMIs) that target signal transduction pathways that attenuate Mcl-1 function, expression, and stability. Our ultimate goal is to use these SMIs in combination with existing Bcl-xL inhibitors to achieve synergistic effects. Furthermore, we aim to expand our evaluation to include existing pre-clinical kinase inhibitors and identify synergistic combinations of inhibitors that target either the Mcl-1 arm or the Bcl-xL arm of the apoptotic pathway, with the rationale that their combined inhibition is necessary for the initiation of programmed cell death (PCD). To develop SMIs we have evaluated compounds using the aminopyrazole scaffold which targets cyclin dependent kinases (CDKs). CDKs have been shown to positively regulate Mcl-1 and, to some extent, Bcl-xL. The aim of this dissertation is to develop CDK inhibitors which indirectly target Mcl-1 and identify kinase inhibitor combinations which target Mcl-1 and Bcl-xL.

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