Date of Award

1-1-2022

Embargo Period

4-20-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Patrick M. Woster

Second Advisor

Pieter B. Burger

Third Advisor

Nathan G. Dolloff

Fourth Advisor

Yuri K. Peterson

Fifth Advisor

Jessica E. Thaxton

Abstract

High-risk neuroblastoma (NB) accounts for 15% of all pediatric cancer deaths. Refractory disease for high-risk NB patients is attributed to chemotherapy resistance and immunotherapy failure. The poor prognosis for high-risk NB patients demonstrates an unmet medical need for the development of new, more efficacious and accessible therapeutics. CD38 is an immunomodulating protein that is expressed constitutively on natural killer (NK) cells and other immune cells in the tumor microenvironment (TME). Furthermore, CD38 over expression is implicated in propagating an immunosuppressive milieu within the TME. Through virtual and biological screening, we have identified drug-like small molecule inhibitors of CD38 with low micromolar IC50 values. We have explored structure activity relationships for CD38 inhibition through derivatization of our most effective hit molecule to develop a new improved compound with lead-like physicochemical properties and improved potency. We have demonstrated that our derivatized inhibitor, compound 21, elicits immunomodulatory effects in NK cells by increasing cell viability by 190 ± 36% in multiple donors and by increasing interferon gamma by 759 ± 45%. Additionally, we have shown that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. In this work, the synthesis and biological evaluation of small molecule CD38 inhibitors specifically for use in NB immunotherapy will be described.

Rights

All rights reserved. Copyright is held by the author.

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