Abstract 5139: Molecular docking exploration of potential RET tyrosine kinase inhibitors at non ATP-binding sites.

Abstract RET (REarranged during Transfection) tyrosine kinase receptor is a transmembrane protein required for the development of neural-crest-derived cells, the urogenital system, and the central and peripheral nervous systems, notably the enteric nervous system. The RET protein has an extracellular domain with a cysteine-rich region and four cadherin-like domains, a transmembrane domain, and an intracellular tyrosine kinase domain, required for RET phosphorylation and downstream signaling. The structure of the RET kinase shares with other tyrosine kinases many conserved functional motifs and regulatory residues that are important for the kinase enzyme function. RET activation requires binding of a glial cell-line-derived neurotrophic factor (GDNF) and a co-receptor of the GDNF family receptors α. Germline mutations of RET, leading to uncontrolled activation, are associated with thyroid cancer, and recently with colorectal and lung cancers, and chronic myelomonocytic leukemia. RET mutations that result in decreased receptor function have been linked to developmental defects, such as Hirschsprung disease and kidney anomalies. The design of receptor tyrosine kinase (RTK) inhibitors has traditionally targeted the enzymes’ highly conserved ATP binding pocket. This approach resulted in the discovery of potent small molecule inhibitors, but with relatively low selectivity. To date there are no RET-specific inhibitors available for therapy, although few small molecule inhibitors are undergoing clinical evaluations as potential RET inhibitors. Since there are important critical regions within the RET molecule (e.g., the substrate binding pocket and activation loop) that contain unique amino acids and structural features, we used the method of molecular docking to virtually screen a diverse library of compounds that potentially target non-ATP binding sites of RET. Known ligands of RET were used to test the success of docking before the library of compounds was screened, docking solutions were inspected and ranked, and best compounds selected for novel structural features and future testing. Multiple comparisons with other known structures of RTK-ligand complexes have been performed in order to identify molecular features that would characterize the discovery of potential RET-specific inhibitors. Citation Format: Adrian C. Nicolescu, Taranjit S. Gujral, Jordan DS Zelt, Lois M. Mulligan. Molecular docking exploration of potential RET tyrosine kinase inhibitors at non ATP-binding sites. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5139. doi:10.1158/1538-7445.AM2013-5139 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

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