Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3
Jennifer Alisa Amrhein, Lena M. Berger, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Amelie Menge, Andreas Krämer, Julia Marie Frischkorn, Benedict‐Tilman Berger, Lewis Elson, Astrid Kaiser, Manfred Schubert‐Zsilavecz, Susanne Müller, Stefan Knapp, Thomas Hanke
Abstract
MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and apoptosis, and its dysregulation has been linked to high-grade tumors. To date, there are no isoform-selective inhibitors that could be used for validating the role of MST3 in tumorigenesis. We designed a series of 3-aminopyrazole-based macrocycles based on the structure of a promiscuous inhibitor. By varying the moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 ( 21c ) was synthesized. JA310 exhibited high cellular potency for MST3 (EC 50 = 106 nM) and excellent kinome-wide selectivity. The crystal structure of the MST3–JA310 complex provided intriguing insights into the binding mode, which is associated with large-scale structural rearrangements. In summary, JA310 demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents the first chemical probe for MST3.