Date of Completion

9-29-2014

Embargo Period

9-29-2015

Keywords

Hedgehog pathway, Vitamin D3, Itraconazole, hybrid analogues, Basal Cell Carcinoma, Medulloblastoma, Gli1, Cyp24A1, Vitamin D Receptor, Smo

Major Advisor

Dr. M. Kyle Hadden

Associate Advisor

Dr. Charles Giardina

Associate Advisor

Dr. Dennis L. Wright

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The Hedgehog (Hh) signaling is an important embryonic developmental pathway normally responsible for tissue growth, differentiation and patterning. However, aberrant activity of this signaling cascade has been implicated in several types of cancer. Therefore, inhibition of the dysregulated pathway is a promising therapeutic target for treating Hh-dependent malignancies such as basal cell carcinoma (BCC) and medulloblastoma (MB). Previous studies resulted in the FDA approval of Vismodegib, a small molecule inhibitor of the Hh pathway, for the treatment of advanced BCC. Similarly, several other small molecule Hh antagonists have progressed into clinical trials. Moreover, several components within the Hh pathway have proven to be druggable in ‘proof-of-concept’ studies. Nonetheless, several challenges in the discovery and development process for small molecules targeting this pathway have been noted. For instance, multiple mechanisms of resistance to Hh inhibitors have been identified. This has prompted extensive search for novel inhibitors that function via mechanisms that will retain activity in the presence of pathway signaling resistant to current therapy. Consequently, a ligand based approach was undertaken to develop Hh inhibitors based on two distinct lead structures namely Vitamin D3 (VD3) and Itraconazole (ITZ). An interdisciplinary approach utilizing synthetic organic chemistry transformations and molecular biology techniques was adopted to study the Hh inhibitory effects of probing relevant biological systems with aforementioned small molecule modulators and their derivatives. Information thus obtained guided the design of improved second-generation Hh inhibitors. A structure-activity-relationship study to identify the Hh inhibitory pharmacophore of VD3 was pursued. Based on the findings, VD3 based anti-Hhanalogues with improved potency and selectivity were designed, synthesized and evaluated. Next, a synthetic methodology for preparing ITZ derivatives with stereochemically defined hydroxylated side chains was optimized. Preliminary evaluation of resultant hybrid ITZ analogues obtained via this synthetic route identified Hh inhibitors demonstrating nanomolar potencies. Taken together, the preliminary identification of several improved Hh inhibitory scaffolds through these studies will facilitate further comprehensive biological evaluation of the promising derivatives.

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