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Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinase.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-17 , DOI: 10.1016/j.bmcl.2020.127108 Maria A Ortiz 1 , Heather Michaels 2 , Brandon Molina 1 , Sean Toenjes 3 , Jennifer Davis 2 , Guya Diletta Marconi 4 , David Hecht 5 , Jeffrey L Gustafson 3 , F Javier Piedrafita 1 , Adel Nefzi 6
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-17 , DOI: 10.1016/j.bmcl.2020.127108 Maria A Ortiz 1 , Heather Michaels 2 , Brandon Molina 1 , Sean Toenjes 3 , Jennifer Davis 2 , Guya Diletta Marconi 4 , David Hecht 5 , Jeffrey L Gustafson 3 , F Javier Piedrafita 1 , Adel Nefzi 6
Affiliation
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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.
中文翻译：
发现环状胍连接的磺酰胺作为LMTK3激酶的抑制剂。
狐猴酪氨酸激酶3（LMTK3）在多种癌症中均具有致癌性。在乳腺癌中，LMTK3磷酸化并调节雌激素受体-α（ERα）的活性，对于ER阳性细胞的生长至关重要。LMTK3在ER阴性乳腺癌细胞中高表达，并通过整合素β1促进侵袭。LMTK3的丰度和/或高核表达与多种癌症中较短的无病生存时间和总体生存时间有关，这支持LMTK3作为抗癌药物开发的潜在目标。我们试图确定LMTK3的小分子抑制剂，其最终目的是在药理上验证该激酶为癌症的新靶标。我们使用均相时间分辨荧光（HTRF）分析来筛选包含1800万种化合物的基于混合物的组合化学文库。
更新日期：2020-03-19
中文翻译：
发现环状胍连接的磺酰胺作为LMTK3激酶的抑制剂。
狐猴酪氨酸激酶3（LMTK3）在多种癌症中均具有致癌性。在乳腺癌中，LMTK3磷酸化并调节雌激素受体-α（ERα）的活性，对于ER阳性细胞的生长至关重要。LMTK3在ER阴性乳腺癌细胞中高表达，并通过整合素β1促进侵袭。LMTK3的丰度和/或高核表达与多种癌症中较短的无病生存时间和总体生存时间有关，这支持LMTK3作为抗癌药物开发的潜在目标。我们试图确定LMTK3的小分子抑制剂，其最终目的是在药理上验证该激酶为癌症的新靶标。我们使用均相时间分辨荧光（HTRF）分析来筛选包含1800万种化合物的基于混合物的组合化学文库。
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