Synthesis and Optimization of Soluble Quinazoline-based Rok1p Inhibitors
Project Author
Issue Date
2024-04-12
Authors
Fry, Zachary
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First Reader
Betush, Matt
Additional Readers
Nelson, Margaret K.
Persichini, Phillip J.
Persichini, Phillip J.
Keywords
Biochemistry , Drug Design , Small molecule synthesis , Organic Chemistry
Distribution
Abstract
Prostate cancer is among the deadliest and most common forms of cancer in males1. Cancer is often characterized by the modification of expressions of DEAD-Box proteins, proteins with a well conserved Asp (D) - Glu (E) – Ala (A) – Asp (D) motif, several of which are upregulated to keep up with the translational needs of cancer cells2. DDX52 is often upregulated as it is a central part of ribosome synthesis and has been found to be correlated with higher metastasis and death rates of prostate cancer3. Inhibition of this protein may be a potential pathway for cancer therapy as knockdown of genes associated with DDX52 results in decreased cancer growth and metastasis. DDX52 can be modeled using the yeast analog Rok1p, which is structurally similar and allows for easy purchase and testing. Recent research, however, has discovered difficulties in the production of these inhibitors as well as poor inhibition in general. This study aimed to optimize the synthetic and isolation strategies associated with the development of these inhibitors as well as synthesize potential new inhibitors taking advantage of a binding pocket above the ATP-binding pocket via linkages high in polar molecules. Computer modeling suggests that these new 3rd generation inhibitors could be viable drugs, however synthesis of the inhibitors proves difficult due to isolation difficulties. Future experimentation could involve protection of primary amines to ease isolation and eventual testing of the inhibitors against Rok1p.
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Major
Biochemistry
Department
Biochemistry