Explore RSK inhibition in models of heart failure and beyond with BIX 02565: Order now!
31 January 2022
The human ribosomal S6 kinases (RSK) are a family of Ser/Thr protein kinases and increased RSK activation is implicated in the etiology of multiple pathologies, including numerous types of cancers, cardiovascular disease, liver and lung fibrosis, and infection.
BIX 02565 has been characterized as a highly potent inhibitor of the N-terminal kinase domain of the three RSK isoforms expressed in cardiac cells. It showed the best combination of potency, selectivity, and solubility among a panel of molecules and is well suited for both in vitro and in vivo experiments. Generated against human RSK, BIX 02565 shows cross-reactivity to mouse and rat RSK. The overall balanced profile makes it an attractive compound to study the role of RSK kinases.
The RSK isoforms are downstream effectors of the Ras/ERK signaling pathway and specifically modulate sodium–hydrogen exchanger (NHE). One important cardiovascular target of RSK is the Na+/H+ exchanger isoform 1 or NHE1. Transporters such as the NHE are important regulators of intracellular pH. Activation of the NHE in myocardial tissue is crucial for pH maintenance during the early phase of cellular stress. However, over longer periods, this activation of NHE can lead to Ca2+ overload, which has been associated with cardiac hypertrophy. Reducing the activation of NHE while maintaining the cellular pH has been hypothesized as a potential alternative approach, and studies in animal models have shown RSK to potentially be such an activator of NHE.
We are also proud to offer BI-9627, a highly potent NHE1 inhibitor with low drug–drug interaction potential, excellent pharmacokinetics, and good selectivity against NHE2 and NHE3. This allows to study dual inhibition of both targets within the same signal cascade.
You can now order our latest molecule on opnMe, BIX 02565 - an RSK inhibitor, as well as our NHE1 inhibitor BI-9627 free of charge to uncover new insights.
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About BIX 02565:
BIX 02565 is a nanomolar inhibitor of ribosomal S6 kinases (RSKs) isoforms. It has been extensively characterized on a standardized selectivity panel and shows high selectivity compared to other kinases. It further demonstrates inhibition of adrenergic receptor subtypes (α1A, α2A, α1B and β2) and the imidazoline I2 receptor (IC50 values between 0.052 and 1.820 µM). BIX 02565 showed a precipitous and dose-dependent decrease in mean arterial pressure in vivo in a rodent model, which was accompanied by marked bradycardia.
About BI-9627:
BI-9627 is a highly potent NHE1 inhibitor with low drug-drug interaction potential as measured by CYP inhibition, CYP 3A4 inactivation, and PXR mediated CYP 3A4 induction. It shows low hERG potency with concomitant absence of effects in lengthening action potential duration, excellent pharmacokinetics in rodents, and remarkably potent activity in the isolated heart model of ischemia-reperfusion injury. The compound also shows good selectivity against NHE2 and NHE3. BI-0054, a close analog of BI-9627, can be ordered as negative control.
About opnMe:
opnMe.com, the new open innovation portal of Boehringer Ingelheim, aims to accelerate research initiatives to enable new insights of disease biology in areas of high unmet medical need by sharing well-characterized molecules and offer collaborations for science. In the spirit of collaboration, our molecules are provided to the scientific community to help unlock and fulfill their full potential. These molecules are either freely available as “Molecules to Order” or applied via scientific research submissions as “Molecules for Collaboration”. As part of our third pillar, our “opn2EXPERTS” program, we enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs.