Journal Article (Letter)

DKFZ-2023-01174

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2.

Amrhein, J. A. ; Wang, G.DKFZ* ; Berger, B.-T. ; Berger, L. M. ; Kalampaliki, A. D. ; Krämer, A.DKFZ* ; Knapp, S.DKFZ* ; Hanke, T.

2023
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acsmedchemlett.3c00127

Abstract: Bone morphogenetic protein (BMP) signaling is mediated by transmembrane protein kinases that form heterotetramers consisting of type-I and type-II receptors. Upon BMP binding, the constitutively active type-II receptors activate specific type-I receptors by transphosphorylation, resulting in the phosphorylation of SMAD effector proteins. Drug discovery in the receptor tyrosine kinase-like (TKL) family has largely focused on type-I receptors, with few inhibitors that have been published targeting type-II receptors. BMPR2 is involved in several diseases, most notably pulmonary arterial hypertension, but also contributes to Alzheimer's disease and cancer. Here, we report that macrocyclization of the promiscuous inhibitor 1, based on a 3-amino-1H-pyrazole hinge binding moiety, led to a selective and potent BMPR2 inhibitor 8a.

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Contributing Institute(s):

1. DKTK FM zentral (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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