Phenotypic Based Drug Discovery, Design, Synthesis, and Optimization of: (i.) Small Molecules that Inhibit Candida Albicans Biofilm Formation; and (ii.) Capsazepine Analogs with Anti-proliferative Activity Against Oral Squamous Cell Carcinoma




Valdez, Matthew Christopher

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Using phenotypical drug screening, iterative drug design cycles, and an emphasis on the selection of compounds with favorable physicochemical properties (PCPs), a number of highly potent and novel small molecules have been synthesized, evaluated, and analyzed in two separate collaborative projects for use as anti-fungal and anti-cancer drugs.

Candida albicans infections are responsible for up to 30,000 deaths in the US annually, especially in immunocompromised patients in a hospital setting. Current therapies for the treatment of these infections are associated with severe side effects and have acted as a selective force for the evolution of the organism, resulting in a growing number of reported cases in which traditional therapy is noted to be ineffective. In conjunction with the STCEID (South Texas Center for Emerging Infectious Disease), the CIDD (The Center for Innovative Drug Discovery) has developed two series of small molecules that target a virulence factor involved in the formation of a biolfim by the Candida albicans organism. By targeting this virulence factor, the normally commensal organism is disarmed of its ability to develop into a pathogen without being eliminated, thus limiting disruption to the microbiome.

Each year in the US, oral squamous cell carcinoma kills approximately 10,000 people. Unfortunately, no efficacious therapies have been developed over the last 40 years resulting in little improvement in overall survivorship of the disease. Capsazepine, a previously discovered synthetic molecule recognized to cause TRPV1 (Transient Receptor Potential Cation Channel Subfamily V Member 1) inhibition, has been shown to display moderate anti-proliferative activity against OSCC (Oral Squamous Cell Carcinoma). Through work with our collaborators at the University of Texas Health Science Center at San Antonio, the anti-proliferative activity of synthetic analogs has been improved relative to Capsazepine by up to 120-fold. Two of these novel compounds lacked TRPV1 activity at therapeutic doses, while still showing activity against multiple cancer cell lines, and additional studies found these compounds to be safe and efficacious in a rat model. These results are demonstrative of development of promising novel anti-cancer therapeutic candidates.


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Drug Development, Drug Discovery, Medicinal Chemistry, Organic Synthesis, Phenotypical Screening, Small Molecules