AI Article Synopsis
- - BMP signaling is activated when the type-II receptors bind BMP and then stimulate type-I receptors, which leads to the phosphorylation of SMAD proteins, crucial for cellular functions.
- - Most drug development has concentrated on type-I receptors in the receptor tyrosine kinase-like family, with limited focus on type-II receptors, which include BMPR2.
- - A newly designed inhibitor, through a method called macrocyclization, has been created to selectively target BMPR2, showing potential for treating diseases like pulmonary arterial hypertension, Alzheimer's, and cancer.
Article 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 , based on a 3-amino-1-pyrazole hinge binding moiety, led to a selective and potent BMPR2 inhibitor .
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258821 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.3c00127 | DOI Listing |
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