Mechanistic insights on novel small molecule allosteric activators of cGMP-dependent protein kinase PKG1α.

ABSTRACT: cGMP-dependent protein kinase (PKG) represents a compelling drug target for treatment of cardiovascular diseases. PKG1 is the major effector of beneficial cGMP signaling which is involved in smooth muscle relaxation and vascular tone, inhibition of platelet aggregation and signaling that leads to cardioprotection. In this study, a novel piperidine series of activators previously identified from an ultrahigh-throughput screen were validated to directly bind partially activated PKG1α and subsequently enhance its kinase activity in a concentration-dependent manner. Compounds from initial optimization efforts showed an ability to activate PKG1α independent of the endogenous activator, cGMP. We demonstrate these small molecule activators mimic the effect of cGMP on the kinetic parameters of PKG

SUBMITTER: Tawa P 

PROVIDER: S-EPMC9425037 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature