Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3

  • J Med Chem. 2024 Jan 11;67(1):674-690. doi: 10.1021/acs.jmedchem.3c01980.
Jennifer Alisa Amrhein  1  2 ,  Lena Marie Berger  1  2 ,  Dimitrios-Ilias Balourdas  1  2 ,  Andreas C Joerger  1  2 ,  Amelie Menge  1  2 ,  Andreas Krämer  1  2  3 ,  Julia Marie Frischkorn  1  2 ,  Benedict-Tilman Berger  1  2 ,  Lewis Elson  1  2 ,  Astrid Kaiser  1 ,  Manfred Schubert-Zsilavecz  1 ,  Susanne Müller  1  2 ,  Stefan Knapp  1  2  3 ,  Thomas Hanke  1  2
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2. Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DTKT Site Frankfurt-Mainz 69120 Heidelberg, Germany.
PMID: 38126712 DOI: 10.1021/acs.jmedchem.3c01980
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 (EC50 = 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.

Products