IN VITRO PHARMACOKINETIC PROFILING OF WAIXENICIN A AND ANALOGUES FOR PRECLINICAL DEVELOPMENT OF THERAPEUTICS FOR NEONATAL HIBI
Hypoxic-ischemic brain injury (HIBI) in neonates is a major cause of acute mortality and chronic neurological morbidity in infants, requiring new therapeutic interventions. Pharmacological or genetic suppression of the channel kinase TRPM7 during ischemic events is neuroprotective in vivo. Waixenicin A (waixA), a metabolite of a soft coral endemic to Hawaii, is the only potent inhibitor of TRPM7 that is highly specific and active both in vitro and in vivo. WaixA represents an opportunity to develop a pharmacophore as a therapeutic intervention in HIBI. We have organized an interdisciplinary team whose overarching goals are to (1) fully describe the neuroprotective role of TRPM7 suppression in vivo before, during, and after HIBI; (2) deliver an understanding of the waixA pharmacophore through synthesis; and (3) determine the full mechanisms of TRPM7 inhibition of waixA and synthetic analogs. The goal of the research proposed here is to investigate the in vitro pharmacokinetic characteristics of waixA to support the goals above and strengthen the preliminary data for other interdisciplinary team proposals.