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

Autor:	Amrhein JA; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Berger LM; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Balourdas DI; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Joerger AC; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Menge A; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Krämer A; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DTKT Site Frankfurt-Mainz 69120 Heidelberg, Germany., Frischkorn JM; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Berger BT; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Elson L; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Kaiser A; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany., Schubert-Zsilavecz M; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany., Müller S; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Knapp S; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DTKT Site Frankfurt-Mainz 69120 Heidelberg, Germany., Hanke T; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jan 11; Vol. 67 (1), pp. 674-690. Date of Electronic Publication: 2023 Dec 21.
DOI:	10.1021/acs.jmedchem.3c01980
Abstrakt:	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.
Databáze:	MEDLINE
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