Date of Award

10-19-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Darin Jones

Second Advisor

Anindya Ghosh

Abstract

The growth factor receptor tyrosine kinase (RTK) family is a potent inducer of cellular growth. Ligand binding to cognate receptors on plasma membrane induces receptor dimerization and activation, which in turn recruits intracellular molecules for downstream signal transduction. A key signaling pathway activated by growth factor (GF) receptors is the Ras signaling cascade that ultimately leads to cell proliferation. Activation of RTKs leads to the recruitment of adapter protein Grb2, which is constitutively bound to the mammalian homolog of drosophila son of sevenless (SOS), and a guanine exchange factor (GEF) for Ras. The recruitment of the Grb2-SOS complex by activated RTK places the GEF in close proximity to Ras and the exchange of Ras-GDP to Ras-GTP and the initiation of the mitogen-activated protein (MAP) kinase cascade. All RTKs recruit Grb2 either directly or indirectly to their early signaling complex as a means to activate Ras-MAP kinase signaling. Virtual drug screening has identified several dimer interface binding drug-like molecules bridging the two Grb2 protomers which sever the link to SOS that is critical to Ras/MAP kinase activation. The design and synthesis of novel analogs to enhance the binding and stabilization of dimeric Grb2 are presented.

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