Abstract LB-C20: Lead generation and optimisation of a series of novel glutaminase (GLS) inhibitors

Glutamine is an essential nutrient for cancer cells and is used to support cancer cell growth. Glutamine is converted to glutamate by the enzyme glutaminase, which is then converted into alpha-ketoglutarate, a metabolic intermediate within the TCA cycle which serves as a precursor for the biosynthesis of ATP, NADPH, fatty acids, glutathione, nucleic acids and amino acids. As such, we regarded glutaminolysis as a key pathway for therapeutic intervention. At the outset of the project there were several reported inhibitors of glutaminase known in the literature; however, they possess undesirable drug like properties. We describe here our efforts to discover novel inhibitors of glutaminase with a promising development profile. From a high throughput screen of approximately 900,000 compounds in the AstraZeneca collection, we were able to identify three series of glutaminase inhibitors. One of these series has been optimised to deliver cell potent, selective and orally bioavailable inhibitors of glutaminase 1. Citation Format: Mark D. Charles, Ceri Cairnduff, Joanna Brookfield, Verity Sabin, Tennyson Ekwuru, Neil Jones, Attilla Ting, James Smith, Willem Nissink, Ray Finlay, Steve Powell, Susan Critchlow, Richard Ward, Matthew Wood, Linette Ruston, Jon Winter, Ian Hollingsworth. Lead generation and optimisation of a series of novel glutaminase (GLS) inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C20.