Classic galactosemia is a rare genetic metabolic disorder (1/60,000 births) that is characterized by decreased production of galactose-1-phosphate uridyltransferase (GALT), an enzyme responsible for the conversion of galactose-1-phosphate (gal-1-p) to glucose-1-phosphate. The resulting elevated intracellular concentrations of gal-1-p are believed to be the major pathogenic mechanism in classic galactosemia that leads to a myriad of secondary symptoms and, if untreated, death of the patient. Galactokinase (GALK1) is an upstream enzyme in the Leloir pathway that is responsible for conversion of galactose to gal-1-p. Therefore, it is hypothesized that small molecule inhibitors of GALK1 may act to decrease levels of gal-1-p in classic galactosemic patients, leading to a milder disease phenotype and more manageable symptoms.
NCATS has a long-standing collaboration with Dr. Kent Lai (University of Utah) to develop inhibitors of human GALK1 for the treatment of classic galactosemia. Screening and medicinal chemistry efforts have led to the identification of several small molecule GALK1 probes, which potently inhibit GALK1 in vitro, and lower pathogenic gal-1p levels in primary patient fibroblasts.
Ongoing optimization of these inhibitors has led to improved on-target activity, as well as improved absorption, distribution, metabolism and excretion properties. Advanced characterization of these molecules in follow-up models of galactosemia is ongoing, with the goal of validating efficacy in preclinical models of the disease.
Additional background on these joint GALK1 efforts is outlined in the publications listed below. Institutions with interest in this target or the published GALK1 inhibitors are welcome to contact the group for more information.
Please contact Ajit Jadhav (firstname.lastname@example.org) and Kyle Brimacombe (email@example.com) at NCGC/NCATS to inquire further.
Boxer MB, Shen M, Tanega C, et al. Toward Improved Therapy for Classic Galactosemia. 2010 Mar 18 [Updated 2011 Mar 3]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.Available from: http://www.ncbi.nlm.nih.gov/books/NBK56237/
Lai K, Boxer MB and Marabotti A. GALK inhibitors for classic galactosemia. Future Med Chem. 2014: 6(9):1003-15.
Liu L, Tang M, Walsh MJ, et al. Structure activity relationships of human galactokinase inhibitors. Bioorg Med Chem Lett. 2015: 25(3):721-7.