Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2.
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Amrhein JA, Wang G, Berger BT, Berger LM, Kalampaliki AD, Kramer A, Knapp S, Hanke T
Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2.
ACS Med Chem Lett. 2023 May 30;14(6):833-840. doi: 10.1021/acsmedchemlett.3c00127. eCollection 2023 Jun 8.
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- 37312836 [ View in PubMed]
- 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.