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

[Display omitted] 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...

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Published in:Bioorganic & medicinal chemistry letters 2020-05, Vol.30 (9), p.127108-127108, Article 127108
Main 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
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Breast cancer
Combinatorial chemistry
Combinatorial Chemistry Techniques
Drug Discovery
Gene Expression Regulation, Neoplastic - drug effects
Guanidine-linked sulfonamide
Humans
LMTK3
Membrane Proteins - antagonists & inhibitors
Molecular Structure
Neoplasms - metabolism
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Small molecule kinase inhibitors
Small Molecule Libraries
Solid-phase synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127108