M6*
Development of GRK5 Inhibitors for the Treatment of Acute and Chronic Cardiovascular Diseases
Prof. Axel Ullrich, Max-Planck Institute for Biochemistry; Prof. Kristina Lorenz, ISAS; Prof. Johannes Backs, University Hospital of Heidelberg; Dr Bert Klebl, Khanu GmbH on behalf of KHAN-I GmbH & Co. KG (KHAN-I) and Lead Discovery Center GmbH (LDC)
Max-Planck-Innovation GmbH
Challenge
Two separate tracks for acute and chronic heart failure candidates are being pursued, catering to different therapeutic needs and mitigating safety risks. Ongoing collaborations with academic and clinical partners aim to validate these findings and improve understanding of GRK5 inhibitor mechanisms, further strengthening the potential for translational success in human therapies. Safety remains one of the key challenges while developing cardiovascular diseases (CVD) drugs. On the other side, superiority over first-line chronic CVD (e.g. Beta-blockers for heart failure) drugs needs to be shown and finding the right target patient population is also a key challenging factor here.
Technology
G protein–coupled receptor kinase 5 (GRK5) is a member of a family of enzymes that phosphorylate and desensitize activated GPCRs and plays a fundamental pathophysiological role in the heart. Being highly expressed within the myocardium, GRK5 has been shown to be a critical regulator of cardiac GPCR-coupled receptor signaling and was found to be up-regulated in heart failure caused by abnormal hypertrophic stress. In the myocardium, GRK5 is upregulated in heart failure patients and patients with dilated cardiomyopathy resulting in worse disease prognosis and mortality. Besides its canonical role, GRK5 can also translocate to the nucleus of cardiomyocytes where it can exert GPCR-independent effects promoting maladaptive cardiac hypertrophy and dysfunction. It was shown that transgenic mice with cardiomyocyte-specific GRK5 overexpression have increased cardiac hypertrophy and functional impairments, while cardiomyocyte-specific GRK5 knockout mice develop less hypertrophy and maintain better cardiac function after transverse aortic constriction.
Commercial Opportunity
The commercial potential for chronic cardiovascular drugs is quite high due to the global burden of heart disease. Recent statistics indicate a concerning increase in CVD prevalence. More than half a billion people around the world continue to be affected by cardiovascular diseases, which accounted for 20.5 million deaths in 2021 close to a third of all deaths globally and an overall increase on the estimated 121 million CVD deaths. While its prevalence is on the rise, necessitating a deeper understanding of associated risk factors such as hypertension and cardiac hypertrophy. With our first-in-class GRK5 inhibitor project, we present a new mechanism of action not only for acute CVD but also chronic cardiovascular conditions such as heart failure and hypertrophic cardiomyopathy.
Development Status
Assay cascade for the profiling and optimization of GRK5 inhibitors has been successfully established. This includes biochemical, cellular, and in vivo assays that demonstrate both activity and selectivity for GRK5. More than 500 GRK5 inhibitor compounds were evaluated and optimized, giving rise to a frontrunner series. We have developed highly specific and active first-in-class GRK5 inhibitors and shown successful proof of concept in relevant animal models for Takotsubo Cardiomyopathy, Transverse Aortic Constriction and Myocardial Infarction. Frontrunner compounds significantly reduced hypertrophy and improved cardiac function in these experimental models. For acute CVD (such as Takotsubo) we have successfully nominated a preclinical development candidate with an i.v. formulation. To address chronic CVD, the optimization of an orally available analog is underway. Also, investigation of frontrunner compounds in additional in vivo models is ongoing.
Patent Situation
Composition of matter patent application filed in 06.2022.
Further Reading
De Lucia et al., 2021; Eguchi et al., 2021
