A novel serum glucocorticoid regulated kinase 1 inhibitor improves cardiac structure and function in heart failure

Despite the advent of transformative guideline-directed therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide, underscoring an urgent need for novel therapies. Clinical benefits of contemporary interventions (sodium-glucose co-transporter-2 inhibitors, SGLT2i) in HF suggest the importance of metabolic modulation to complement classical neurohormonal blockade in HF pharmacotherapy. Serum glucocorticoid regulated kinase 1 (SGK1) has emerged as a prime stress-induced regulator of multiple metabolic-inflammatory pathways central to HF in model systems, though translation to patients is limited by absence of a selective, efficacious pharmacologic inhibitor. Here, we provide the first demonstration to our knowledge of a novel, phase 2 ready small molecule SGK1 inhibitor (THRV-SGK1i), demonstrating (1) human genetic and tissue evidence linking SGK1 with HF; (2) kinase selectivity, potency, pharmacodynamics, and SGK1 target engagement by THRV-SGK1i; (3) the beneficial effect of THRV-SGK1i on myocardial structure, function, and histopathology in a pressure-overload HF model alone or in combination with SGLT2i. The convergence of human genetic and tissue data, precision discovery-guided drug development, model system studies, and a comprehensive nonclinical safety package provide compelling evidence in support of the planned clinical studies of SGK1 inhibition in clinical HF.