Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinase. Issue 9 (1st May 2020)

• Record Type: Journal Article
• Authors: Ortiz, Maria A.; Michaels, Heather; Molina, Brandon; Toenjes, Sean; Davis, Jennifer; Marconi, Guya Diletta; Hecht, David; Gustafson, Jeffrey L.; Piedrafita, F. Javier; Nefzi, Adel
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 9(2020)
• Publication Date: 2020-05-01
• Subjects: CETSA cellular thermal shift assay -- Cha cyclohexyl alanine -- CRISPR clustered regularly interspaced short palindromic repeats -- DDX5 DEAD-Box helicase 5 -- ERα estrogen receptor alpha -- FBS fetal bovine serum -- FDA food and drug administration -- HTRF homogeneous time resolved fluorescence -- KAP1 KRAB-associated protein 1 -- KD kinase domain -- LMTK3 lemur tyrosine kinase-3 -- MAPK mitogen-activated protein kinase -- PP1α protein phosphatase 1α -- PSL positional scan library -- RCP Rab-coupling protein -- siRNA small interfering RNA -- RTK receptor tyrosine kinase; LMTK3 -- Small molecule kinase inhibitors -- Guanidine-linked sulfonamide -- Breast cancer -- Combinatorial chemistry -- Solid-phase synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127108
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 .