Sander Pascal, Schwalm Martin P, Krämer Andreas, Elson Lewis, Rasch Alexander, Masberg Benedikt, Selig Roland, Sievers-Engler Adrian, Lämmerhofer Michael, Müller Susanne, Knapp Stefan, Albrecht Wolfgang, Laufer Stefan A
Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
J Med Chem. 2025 Jan 9;68(1):674-694. doi: 10.1021/acs.jmedchem.4c02552. Epub 2024 Dec 16.
The human kinome has tremendous medical potential. In the past decade, mixed-lineage protein kinase 3 (MLK3) has emerged as an interesting and druggable target in oncogenic signaling. The important role of MLK3 has been demonstrated in several types of cancer. In a target hopping example we started with the focal adhesion kinase (FAK) inhibitor PF-431396 (), which shows off-target activity toward MLK3. We were able to develop highly active compounds in the single digit nanomolar range for MLK3. Furthermore, we achieved a dramatic shift in selectivity from FAK to MLK3. Here we present a new chemical class of MLK3 inhibitors, including our lead compound with an outstanding IC value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.
人类激酶组具有巨大的医学潜力。在过去十年中，混合谱系蛋白激酶3（MLK3）已成为致癌信号传导中一个有趣且可成药的靶点。MLK3的重要作用已在多种癌症类型中得到证实。在一个靶点跳跃的实例中，我们从粘着斑激酶（FAK）抑制剂PF - 431396开始，该抑制剂对MLK3表现出脱靶活性。我们能够开发出对MLK3具有高活性的化合物，其活性范围在个位数纳摩尔级别。此外，我们实现了从FAK到MLK3的选择性的显著转变。在此，我们展示了一类新的MLK3抑制剂，包括我们的先导化合物，其在生化MLK3测定中具有小于1 nM的出色IC值，同时在激酶组范围内具有选择性。
