Second‐generation prokineticin PKR ₁ receptor agonists: Advancing cardioprotection against chemotherapy‐induced toxicity

Background and purpose Anthracycline‐induced cardiotoxicity, particularly from doxorubicin, remains a major limitation in cancer therapy, contributing to heart failure and long‐term morbidity. Prokineticin receptor‐1 (PKR 1 ), involved in cardiomyocyte survival and anti‐fibrotic signalling, represents a promising therapeutic target. This study evaluated the cardioprotective potential of IS39, a novel non‐peptide PKR 1 agonist, in models of doxorubicin‐induced cardiac injury. Experimental approach In silico ADME–toxicity profiling, scaffold optimisation and molecular docking were used to refine non‐peptide PKR 1 agonists, replacing the dehydroamide moiety of first‐generation compounds with a D‐aminoacyl group to enhance metabolic stability. The lead compound IS39 was evaluated in vitro in primary cardiomyocytes and in vivo in a murine model of doxorubicin‐induced cardiotoxicity. Parallel studies assessed potential interference with doxorubicin antitumour activity in breast cancer cell lines and 3D tumour spheroids. Endpoints included cardiomyocyte viability, oxidative stress, fibrotic markers, cardiac function, histopathology and systemic tolerability. Key results IS39 selectively activated PKR 1 , reduced reactive oxygen species, suppressed profibrotic gene expression and protected cardiomyocytes from doxorubicin‐induced cytotoxicity in vitro. These effects were abolished by PKR 1 knockdown or antagonism, confirming on‐target activity, and IS39 did not impair doxorubicin antitumour efficacy. In vivo, IS39 preserved left ventricular ejection fraction, attenuated myocardial fibrosis and apoptosis, and improved cardiac morphology. However, systemic IS39 administration exacerbated doxorubicin‐associated weight loss and did not improve overall survival. Conclusions and implications IS39 confers cardioprotection via PKR1‐mediated antioxidant and antifibrotic mechanisms. Despite systemic tolerability limitations, these findings support PKR1 as a therapeutic target and justify development of tissue‐selective PKR1 agonists for cardio‐oncology applications.