From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4).

Philip Klövekorn, Bent Pfaffenrot, Michael Juchum, Roland Selig, Wolfgang Albrecht, Lars Zender, Stefan A Laufer

European journal of medicinal chemistry 2021 Jan 15

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The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAFV600E inhibitor PLX4032 (8). Applying an iterative multi-parameter optimization process we carved out essential structural features yielding in compounds with a low nanomolar affinity for MKK4 and excellent selectivity profiles against the main off-targets MKK7 and JNK1, which, upon relevant inhibition, would totally abrogate the pro-regenerative effect of MKK4 inhibition, as well as against the off-targets MAP4K5, ZAK and BRAF with selectivity factors ranging from 40 to 430 for our best-balanced compounds 70 and 73. Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Citation

Philip Klövekorn, Bent Pfaffenrot, Michael Juchum, Roland Selig, Wolfgang Albrecht, Lars Zender, Stefan A Laufer. From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4). European journal of medicinal chemistry. 2021 Jan 15;210:112963