8QLQ

Human MST3 (STK24) kinase in complex with macrocyclic inhibitor JA310

Summary for 8QLQ

• Entry DOI: 10.2210/pdb8qlq/pdb
• Descriptor: Serine/threonine-protein kinase 24, macrocyclic inhibitor, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: selective kinase inhibitors, macrocyclic inhibitors, structure-guided drug design, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34959.10

Authors

Balourdas, D.I.,Amrhein, J.A.,Hanke, T.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2023-09-20, release date: 2023-11-08, Last modification date: 2024-05-29)

Primary citation

Amrhein, J.A.,Berger, L.M.,Balourdas, D.I.,Joerger, A.C.,Menge, A.,Kramer, A.,Frischkorn, J.M.,Berger, B.T.,Elson, L.,Kaiser, A.,Schubert-Zsilavecz, M.,Muller, S.,Knapp, S.,Hanke, T.
Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3.
J.Med.Chem., 67:674-690, 2024

PubMed 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 () was synthesized. JA310 exhibited high cellular potency for MST3 (EC = 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.

PubMed: 38126712
DOI: 10.1021/acs.jmedchem.3c01980

Experimental method

X-RAY DIFFRACTION (1.64 Å)