Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinase.

Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinase. Bioorg Med Chem Lett. 2020 Mar 17;:127108 Authors: Ortiz MA, Michaels H, Molina B, Toenjes S, Davis J, Diletta Marconi G, Hecht D, Gustafson JL, Javier Piedrafita F, Nefzi A Abstract Lemur tyrosine kinase 3 (LMTK3) is oncogenic in various cancers. In breast cancer, LMTK3 phosphorylates and modulates the activity of estrogen receptor-α (ERα) and is essential for the growth of ER-positive cells. LMTK3 is highly expressed in ER-negative breast cancer cells, where it promotes invasion via integrin β1. LMTK3 abundance and/or high nuclear expression have been linked to shorter disease free and overall survival time in a variety of cancers, supporting LMTK3 as a potential target for anticancer drug development. We sought to identify small molecule inhibitors of LMTK3 with the ultimate goal to pharmacologically validate this kinase as a novel target in cancer. We used a homogeneous time resolve fluorescence (HTRF) assay to screen a collection of mixture-based combinatorial chemical libraries containing over 18 million compounds. We identified several cyclic guanidine-linked sulfonamides with sub-micromolar activity and evaluated their binding mode using a 3D homology model of the LMTK3 KD. PMID: 32192797 [PubMed - as supplied by publisher]
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research