Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 1 vom: 11. Jan., Seite 674-690 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Amrhein, Jennifer Alisa [VerfasserIn] |
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| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 12.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c01980 |
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| funding: |
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| PPN (Katalog-ID): |
NLM366173715 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Berger, Lena Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Balourdas, Dimitrios-Ilias |e verfasserin |4 aut | |
| 700 | 1 | |a Joerger, Andreas C |e verfasserin |4 aut | |
| 700 | 1 | |a Menge, Amelie |e verfasserin |4 aut | |
| 700 | 1 | |a Krämer, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Frischkorn, Julia Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Benedict-Tilman |e verfasserin |4 aut | |
| 700 | 1 | |a Elson, Lewis |e verfasserin |4 aut | |
| 700 | 1 | |a Kaiser, Astrid |e verfasserin |4 aut | |
| 700 | 1 | |a Schubert-Zsilavecz, Manfred |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Knapp, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Hanke, Thomas |e verfasserin |4 aut | |
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