Graduation Date

Spring 5-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Paul C. Trippier

Second Advisor

Corey R. Hopkins

Third Advisor

Daryl J. Murry

Fourth Advisor

Sidharth Mahapatra

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children. Among its molecular subgroups, Group 3 MB (G3MB) is the most aggressive and linked to a high potential for metastasis, poor prognosis, and limited survival despite intensive multimodal therapy. Current treatments, which include maximal surgical removal followed by craniospinal irradiation (CSI) and chemotherapy, have improved outcomes; however, they often cause severe lifelong neurocognitive, endocrine, and psychological toxicities. These limitations underscore an urgent need for more effective and safer targeted therapies.

B7 homolog 3 (B7-H3), an immune checkpoint protein in the B7 family, is highly overexpressed in G3MB and promotes tumor growth, immune escape, and metastasis. Although B7-H3-targeting biologics, including monoclonal antibodies (mAbs) and Chimeric Antigen Receptor (CAR) T-cell therapies, have shown promising antitumor effects in preclinical studies, their use is limited by immune-related toxicities, poor ability to cross the blood–brain barrier, and high manufacturing costs. In contrast, small–molecule inhibitors have advantages such as better tumor and brain penetration, oral bioavailability, adjustable pharmacokinetics, and lower systemic toxicity. However, to date,  no small molecule inhibitors targeting B7-H3 have been reported.

In this dissertation, we aimed to identify and develop the first small molecule inhibitors of B7-H3. The crystal structure of murine B7-H3, which shares high sequence similarity with the human protein, was used to create a homology model for structure guided ligand design. A structure-based virtual screening of 100,000 compounds identified 113 hits, two of which (2.1 and 3.1) were resynthesized and evaluated in the G3MB cell line HDMB-03, exhibiting low micromolar cytotoxicity and evidence of target engagement. Subsequent structure–activity relationship optimization led to the design, synthesis, and biological evaluation of more than 100 analogs, resulting in five lead compounds with nanomolar cellular activity. These candidates are currently being further characterized for brain permeability, metabolic stability, and selectivity to advance druglike molecules into in vivo efficacy studies. We expect that continued SAR refinement of these scaffolds, along with mechanistic studies to understand the underlying molecular and signaling pathways, will further improve their anticancer efficacy and support the development of a new class of targeted therapies for medulloblastoma.

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