Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1α.
J Med Chem
; 65(15): 10318-10340, 2022 08 11.
Article
em En
| MEDLINE
| ID: mdl-35878399
ABSTRACT
Activation of PKG1α is a compelling strategy for the treatment of cardiovascular diseases. As the main effector of cyclic guanosine monophosphate (cGMP), activation of PKG1α induces smooth muscle relaxation in blood vessels, lowers pulmonary blood pressure, prevents platelet aggregation, and protects against cardiac stress. The development of activators has been mostly limited to cGMP mimetics and synthetic peptides. Described herein is the optimization of a piperidine series of small molecules to yield activators that demonstrate in vitro phosphorylation of vasodilator-stimulated phosphoprotein as well as antiproliferative effects in human pulmonary arterial smooth muscle cells. Hydrogen/deuterium exchange mass spectrometry experiments with the small molecule activators revealed a mechanism of action consistent with cGMP-induced activation, and an X-ray co-crystal structure with a construct encompassing the regulatory domains illustrated a binding mode in an allosteric pocket proximal to the low-affinity cyclic nucleotide-binding domain.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
GMP Cíclico
/
Proteína Quinase Dependente de GMP Cíclico Tipo I
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article