Therapeutics Focus and Development

Our development plan includes advancing our hits into lead generation by combining fragment- and structure-based drug discovery with innovative computational chemistry, followed by synthesis of elaborated compounds and iterative cycles of lead optimization driven by biophysics, biochemistry and protein X-ray crystallography, leading to optimization of potency and toxicological profiles. Currently, our effort is centered on proteins that participate in the DNA Damage Response (DDR), an elaborate network that involves elements of damage recognition, cellular signalling, checkpoint regulation, and when possible, resolution of unwanted DNA modification or intermediate through the action of helicases, polymerases, and nucleases, to name a few.  The DDR also plays a critical role in determining cellular fate, such as senescence or apoptosis.  DNA repair, more precisely, consists of distinct pathways that recognize and correct a specific subset of damage types, with the major repair mechanisms including:  mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), and recombinational repair, such as homologous recombination (HR).  Collectively, these systems play important roles in disease etiology, particularly cancer, as well as therapeutic responses.  Our targets (see Pipeline) APE1 and UNG are components of the BER pathway, a system important against the lethal effects of spontaneous hydrolytic, enzyme-derived, oxidative and alkylative DNA damage, commonly generated by therapeutic agents like ionizing radiation, nucleoside analogs, and temozolomide; FEN1 also functions in BER, while participating in other DNA transactions, namely DNA replication, a process that is particularly active in cancerous cells; WRN participates in the resolution of complex DNA intermediates, such as seen during chromosome duplication or recombinational repair; and ExoN participates in mismatch repair (MMR) of a viral genome.

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