Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1α.
Victor W MakAkash M PatelRose YenJennifer HanisakYeon-Hee LimJianming BaoRong ZhengW Michael SeganishYang YuDavid R HealyAimie OgawaZhao RenAileen SorianoGrigori P ErmakovMaribel BeaumontEssam MetwallyAlan C ChengAndreas VerrasThierry FischmannMatthias ZebischH Leonardo SilvestrePaul A McEwanJohn BarkerPaul ReardenThomas J GreshockPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- small molecule
- smooth muscle
- crystal structure
- nitric oxide
- protein kinase
- blood pressure
- mass spectrometry
- pulmonary hypertension
- cardiovascular disease
- endothelial cells
- high resolution
- protein protein
- magnetic resonance imaging
- liquid chromatography
- heart failure
- high glucose
- transcription factor
- left ventricular
- type diabetes
- capillary electrophoresis
- single cell
- magnetic resonance
- regulatory t cells
- blood glucose
- mouse model
- hypertensive patients
- immune response
- amino acid
- high performance liquid chromatography
- drug induced
- ms ms
- single molecule
- adipose tissue
- induced pluripotent stem cells
- gas chromatography
- heat stress
- replacement therapy
- simultaneous determination
- weight loss