David Crich, DèsSc, Georgia Research Alliance and David Chu Eminent Scholar in Drug Design in Pharmaceutical and Biomedical Sciences, was awarded a new $2,000,000 R01 grant to research and develop more effective and safer next generation aminoglycoside antibiotics (AGAs). “Permanent hearing loss and balance disruptions are shockingly common side effects of aminoglycoside antibiotics that effect up to 20% of all patients who receive them,” explained Dr. Crich, who was recently named the American Chemical Society’s 2024 James Flack Norris Award Recipient in Physical Organic Chemistry. Current AGAs also can cause kidney damage and are increasingly susceptible to bacterial resistance, limiting their use against complex, virulent pathogens that demonstrate multi-drug resistance. With this new grant, Dr. Crich’s lab will design, synthesize and evaluate two series of next generation AGA derivatives building on previous structure-activity relationships established in his laboratory.
Dr. Crich and his team also recently published a paper in the Journal of Medicinal Chemistry reporting on research that resulted in the discovery of a small molecule drug candidate for metastatic non-small-cell lung cancer. The title of the paper is “Discovery of a Hydroxylamine-Base Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer.”
According to Dr. Crich, non-small cell lung cancer (NSCLC) is a major cause of death worldwide. Up to 30% of NSCLC patients carry activating mutations in the epidermal growth factor receptor (EGFR) and so are sensitized to treatment by tyrosine kinase inhibitors (TKIs) such as Gefinitib. Unfortunately, up to 40% of NSCLC patients develop brain metatheses, which cannot be treated effectively by Gefinitib and other TKIs due to their poor penetration of the blood brain barrier (BBB). In the recent Journal of Medicinal Chemistry paper, Dr. Crich, his Chemistry graduate student Jarvis Hill and their collaborator Dr. Robert Jones address this important limitation of EGFR TKIs, through the development of a fully BBB penetrant analog of Gefinitib with demonstrated efficacy in a mouse model of a brain metastatic mutation activated EGFR positive NSCLC. To achieve this breakthrough, the team inserted a novel bioisostere based on a trisubstituted hydroxylamine moiety into a side chain of Gefinitib in such a way as to modify the drug’s pharmacokinetics and enhance its BBB penetration without loss of activity or significant increase in molecular weight. The pharmaceutical industry has long eschewed the use of the hydroxylamine moiety in drug design believing it to be mutagenic, but mechanistic considerations lead Crich and his team to the conclusion that this moratorium on hydroxylamine use is an over-extrapolation from a relatively small data set and that trisubstituted hydroxylamines would not be mutagenic, as they amply demonstrate in their paper. Thus, the research not only provides a promising lead compound for the treatment of EGFR positive NSCLC with brain metastases but also shifts the paradigm with respect to the use of trisubstituted hydroxylamines in drug discovery in a broader sense. The team is hoping to advance their Gefinitib analog towards clinic trials and to apply their hydroxylamine concept to other disease states and drug classes through the aegis of Quintet Pharmaceuticals, a start-up they cofounded. Aspects of this work enjoyed the support of the National Institute of General Medical Sciences of the NIH and the Georgia Research Alliance.
