8 research outputs found
Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine
In heart failure, the β-adrenergic
receptors (βARs)
become desensitized and uncoupled from heterotrimeric G proteins.
This process is initiated by G protein-coupled receptor kinases (GRKs),
some of which are upregulated in the failing heart, making them desirable
therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine,
was previously identified as a GRK2 inhibitor. Utilizing a structure-based
drug design approach, we modified paroxetine to generate a small compound
library. Included in this series is a highly potent and selective
GRK2 inhibitor, <b>14as</b>, with an IC<sub>50</sub> of 30 nM
against GRK2 and greater than 230-fold selectivity over other GRKs
and kinases. Furthermore, <b>14as</b> showed a 100-fold improvement
in cardiomyocyte contractility assays over paroxetine and a plasma
concentration higher than its IC<sub>50</sub> for over 7 h. Three
of these inhibitors, including <b>14as</b>, were additionally
crystallized in complex with GRK2 to give insights into the structural
determinants of potency and selectivity of these inhibitors
Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors
G protein-coupled
receptors (GPCRs) are central to many physiological
processes. Regulation of this superfamily of receptors is controlled
by GPCR kinases (GRKs), some of which have been implicated in heart
failure. GSK180736A, developed as a Rho-associated coiled-coil kinase
1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized
in the active site. Guided by its binding pose overlaid with the binding
pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid
inhibitors was developed. This campaign produced several compounds
possessing high potency and selectivity for GRK2 over other GRK subfamilies,
PKA, and ROCK1. The most selective compound, <b>12n</b> (CCG-224406),
had an IC<sub>50</sub> for GRK2 of 130 nM, >700-fold selectivity
over
other GRK subfamilies, and no detectable inhibition of ROCK1. Four
of the new inhibitors were crystallized with GRK2 to give molecular
insights into the binding and kinase selectivity of this class of
inhibitors
Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors
G protein-coupled
receptors (GPCRs) are central to many physiological
processes. Regulation of this superfamily of receptors is controlled
by GPCR kinases (GRKs), some of which have been implicated in heart
failure. GSK180736A, developed as a Rho-associated coiled-coil kinase
1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized
in the active site. Guided by its binding pose overlaid with the binding
pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid
inhibitors was developed. This campaign produced several compounds
possessing high potency and selectivity for GRK2 over other GRK subfamilies,
PKA, and ROCK1. The most selective compound, <b>12n</b> (CCG-224406),
had an IC<sub>50</sub> for GRK2 of 130 nM, >700-fold selectivity
over
other GRK subfamilies, and no detectable inhibition of ROCK1. Four
of the new inhibitors were crystallized with GRK2 to give molecular
insights into the binding and kinase selectivity of this class of
inhibitors
Clonal hematopoiesis in sickle cell disease.
BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH