The project, funded by the German Federal Ministry of Education and Research under grant 03INT703AB, ran from 1 January 2020 to 30 June 2023 and was carried out by the Leibniz Institute for Analytical Sciences (ISAS) in cooperation with the Leibniz Institute for Drug Control (LDC). The overarching aim was to develop orally available, selective inhibitors of G‑protein‑coupled receptor kinase 5 (GRK5) for the treatment of heart failure and pathological cardiac hypertrophy. GRK5 is a kinase that, unlike other cardiac GRKs, can translocate to the nucleus under stress conditions such as chronic pressure overload or sympathetic activation, thereby contributing to maladaptive cardiac remodeling. Prior to this work no selective GRK5 inhibitors had entered clinical development, and most research had focused on GRK2.

The LDC supplied two lead compounds identified through a proprietary low‑nanomolar screening platform. ISAS performed a comprehensive pre‑clinical evaluation of these frontrunners. In vitro assays were established to assess β‑adrenergic signalling, contractility, arrhythmogenic potential and hypertrophic responses in cultured cardiomyocytes. These assays confirmed that the compounds effectively inhibited GRK5 activity without significant off‑target effects on GRK2 or other kinases. In vivo, the compounds were tested in two mouse models: transverse aortic constriction (TAC) to induce pressure‑overload hypertrophy and a myocardial infarction model to mimic ischemic injury. Both preventive and therapeutic dosing regimens were evaluated. The results showed a marked reduction in left‑ventricular mass and improvement in ejection fraction compared with vehicle controls. Survival analysis revealed a statistically significant increase in the proportion of mice reaching the study endpoint in the treated groups. These findings demonstrate that pharmacological inhibition of GRK5 can attenuate pathological cardiac growth and preserve function in acute and chronic settings.

Following the in vivo success, the lead molecules were chemically modified to enhance oral bioavailability. The oral derivatives were administered therapeutically in the TAC model, and preliminary data indicate that they retain efficacy in reducing hypertrophy and improving cardiac output. Detailed pharmacokinetic and tolerability studies have been completed, showing favourable absorption and a low toxicity profile. The project also established a set of in vitro assays that can be used in future screening campaigns to rapidly identify and exclude cardiotoxic candidates, thereby accelerating the pre‑clinical pipeline.

Collaboration between ISAS and LDC was central to the project’s progress. ISAS provided the animal facilities, in vivo expertise, and analytical chemistry support, while LDC contributed the lead chemistry, medicinal chemistry optimization, and intellectual property management. The project was coordinated within the BIO.NRW consortium, which facilitated data sharing and integrated the work with other cardiovascular research initiatives. The funding from BMBF covered all experimental costs, personnel, and consumables, and the project adhered to the planned milestones, with all work packages completed on schedule. The outcomes of this research lay the groundwork for the next phase of development, where the most promising oral GRK5 inhibitor candidates will be advanced toward clinical testing for heart failure and hypertrophic cardiomyopathy.