TY  - JOUR
AU  - Amrhein, Jennifer A
AU  - Wang, Guiqun
AU  - Berger, Benedict-Tilman
AU  - Berger, Lena M
AU  - Kalampaliki, Amalia D
AU  - Krämer, Andreas
AU  - Knapp, Stefan
AU  - Hanke, Thomas
TI  - Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2.
JO  - ACS medicinal chemistry letters
VL  - 14
IS  - 6
SN  - 1948-5875
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2023-01174
SP  - 833 - 840
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37312836
C2  - pmc:PMC10258821
DO  - DOI:10.1021/acsmedchemlett.3c00127
UR  - https://inrepo02.dkfz.de/record/276862
ER  -