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DTSTART;TZID="Pacific Time (US & Canada)":20260727T093000
DTEND;TZID="Pacific Time (US & Canada)":20260727T103000
SUMMARY:Chemistry Dissertation Defense – Ryanne Ballard
LOCATION:Online
DESCRIPTION:Speaker: Ryanne Ballard\n\nGroup: Dr. Cliff Berkman\n\nTitle: THE CHEMICAL VERSATILITY AND BIOLOGICAL RELEVANCE OF PHOSPHORAMIDATES IN CANCER\n\nAbstract\n\nPhosphoramidates play diverse and multifaceted roles in cancer biology. From non-canonical phosphorylation events arising from disease-associated mutations and exposure to organophosphorus (OP) toxicants to the exploitation of their pH-sensitive properties for controlled drug delivery, phosphoramidates are involved in multiple stages of cancer development and treatment.\n\nExposure to OP toxicants, including pesticides and Class V/G nerve agents, results in the formation of phosphoramidate intermediates that can undergo traceless isopeptide cross-linking, a process that may contribute to long-term adverse health effects such as cancer. In parallel, non-canonical phosphorylation of amino acid residues such as lysine, aspartate, and glutamate have been increasingly identified across a broad range of cancer models. Although the biological functions and consequences of many of these phosphorylation events remain poorly understood, their prevalence and potential pathological significance underscore the importance of defining the kinetics, hydrolysis, and stability of these phosphoramidate modifications. Progress in this area has been limited by the intrinsic lability of native phosphoramidate-containing residues, resulting in a lack of literature pertaining to that of authentic phosphorylated lysine (pLys), aspartate (pAsp), and glutamate (pGlu) standards for biochemical investigation. This thesis describes the synthesis of authentic pLys-containing peptides, representing both internal and C-terminal protein positions, through orthogonal protecting group strategies and liquid-phase peptide synthesis. Using 31P NMR spectroscopy in combination with high-performance liquid chromatography (HPLC), we established kinetic stability profiles for authentic pLys residues across a range of physiologically relevant pH conditions.\n\nBuilding upon mechanistic insights obtained from first- and second-generation stimuli-responsive drug conjugates, paired with the kinetic characterization of phosphoramidates under physiological conditions, our laboratory has exploited the inherent lability of phosphoramidate linkages to develop a library of highly selective, stable, and stimuli-responsive drug conjugates incorporating a range of cytotoxic payloads. However, the intrinsic potency limitations and stoichiometric constraints associated with conventional small-molecule drug conjugates have resulted in only modest therapeutic efficacy for payloads such as SN-38, Doxorubicin, Paclitaxel, Docetaxel, and Cabazitaxel. This thesis describes the development of a simplified linker platform and a novel branched linker architecture that addresses these limitations by enabling the conjugation of two cytotoxic payloads to a single targeting ligand, thereby generating small-molecule dual drug conjugates (SMDDCs). Using the previously reported targeting ligand FPO42 in combination with the branched linker system, we achieved selective delivery of both Monomethyl Auristatin E (MMAE) and Exatecan to PSMA-positive (PSMA+) cells, resulting in enhanced cytotoxicity relative to the corresponding single-payload conjugates. Collectively, these findings demonstrate the versatility of phosphoramidate-based linker systems and establish SMDDCs as a promising strategy for improving therapeutic efficacy while overcoming challenges associated with drug potency, solubility, and resistance.
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