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005     20251120135139.0
024 7 _ |a 10.1021/acs.jmedchem.4c02552
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100 1 _ |a Sander, Pascal
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245 _ _ |a Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example.
260 _ _ |a Washington, DC
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500 _ _ |a 2025, 68, 1, 674–694
520 _ _ |a 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 (10), 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 37 with an outstanding IC50 value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.
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700 1 _ |a Schwalm, Martin P
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700 1 _ |a Krämer, Andreas
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700 1 _ |a Elson, Lewis
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700 1 _ |a Rasch, Alexander
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700 1 _ |a Masberg, Benedikt
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700 1 _ |a Selig, Roland
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700 1 _ |a Sievers-Engler, Adrian
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700 1 _ |a Lämmerhofer, Michael
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700 1 _ |a Müller, Susanne
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700 1 _ |a Knapp, Stefan
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700 1 _ |a Albrecht, Wolfgang
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700 1 _ |a Laufer, Stefan A
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773 _ _ |a 10.1021/acs.jmedchem.4c02552
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856 4 _ |u https://inrepo02.dkfz.de/record/295900/files/design-synthesis-and-biochemical-evaluation-of-novel-mlk3-inhibitors-a-target-hopping-example.pdf
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