Date of Award
2025
Document Type
Thesis
Degree Name
MS in Pharmaceutical Science
Department
Pharmaceutical Sciences
First Advisor
Jeanette C Perron
Second Advisor
Diane Hardej
Third Advisor
Sabesan Yoganathan
Abstract
Bone morphogenetic proteins (BMPs) are the largest subfamily of the Transforming Growth Factor (TGF)-ß superfamily. BMPs are renowned for their pivotal role in cellular functions such as cell growth, apoptosis, and differentiation. Yet, BMPs have also been attributed to the maintenance of adult tissue homeostasis. BMPs elicit physiological function at the cell membrane via a heterotetrameric complex composed of two Type I and two Type II serine-threonine kinase BMP receptors. Activation of BMP transmembrane receptors results in activation of either canonical (Smad-dependent) and/or non-canonical (Smad-independent) signaling. Given the physiological importance of this intricate communication between receptor activation and induction of intracellular signaling, pathway dysregulation often leads to pathological conditions. Mutations that trigger pathway dysregulation include BMP ligand mutations, which interfere with receptor activation. BMP receptor mutations induce hyperactive or loss-of-function states. Alterations of intracellular pathway components such as Smad proteins interfere with intended cellular responses such as differentiation, enhanced gene expression, migration, cytoskeletal rearrangements, and more. Given the contributory role of perturbed BMP signaling and disease induction, understanding the underlying mechanisms of BMP signaling is of great clinical significance. Currently, recombinant human BMPs (rBMPs) are clinically approved treatments for BMP-associated pathologies such as Fibrodysplasia Ossificans Progressiva (FOP) and Pulmonary Arterial Hypertension (PAH). However, treatment with recombinant protein is not nearly an optimal therapeutic approach given the high doses necessary to achieve efficacy, high production costs, and potential immunogenic responses. Therefore, the development of agents that counteract these limitations associated with rBMPs is of high importance. Identification of therapeutic alternatives begins with identifying what drives BMP receptor agonism. Previous work demonstrated the stimulatory propensity of novel benzimidazole-containing molecules. Indole-benzimidazoles, SY-LB-35 and SY-LB-57, displayed potent receptor agonism and robust activation of both canonical and non-canonical pathway signaling. Furthermore, the work in the present investigation highlights the involvement of benzimidazole and other scaffold modifications that enhance receptor agonism. The work presented in this investigation supports the conjecture that benzimidazole aids in trafficking small molecules to the BMP receptor and the bulkiness of the small molecules interferes with the ability to cover the surface area of the receptor to drive activation of intracellular signaling.
Recommended Citation
Stewart, Maleka T., "IDENTIFICATION OF PHARMACOPHORE MODIFICATIONS THAT ENHANCE BMP-RECEPTOR AGONISM, AN INVESTIGATION TO UNDERSTAND THE DEVELOPMENT OF POTENTIAL THERAPEUTIC INTERVENTIONS" (2025). Theses and Dissertations. 898.
https://scholar.stjohns.edu/theses_dissertations/898