Alyssa Grogan , Robin M. Perelli , Seungkirl Ahn , Haoran Jiang , Arun Jyothidasan , Damini Sood , Chongzhao You , David I. Israel , Alex Shaginian , Qiuxia Chen , Jian Liu , Jialu Wang , Jan Steyaert , Alem W. Kahsai , Andrew P. Landstrom , Robert J. Lefkowitz , Howard A. Rockman

The Journal of Clinical Investigation 

DOI: 10.1172/jci190252

Abstract

Orthosteric β-blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by the development of adverse effects such as fatigue, hypotension, and reduced exercise capacity, due in part to the nonselective inhibition of multiple βAR subtypes. These challenges are particularly problematic in treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease characterized by lethal tachyarrhythmias directly triggered by cardiac β₁AR activation. To identify small molecule allosteric modulators of the β₁AR that could offer enhanced subtype specificity and robust functional antagonism of β₁AR-mediated signaling, we conducted a DNA-encoded small molecule library screen and discovered Compound 11 (C11). C11 selectively potentiates the binding affinity of orthosteric agonists to the β₁AR while potently inhibiting downstream signaling following β₁AR activation. Moreover, C11 prevents agonist-induced spontaneous contractile activity, Ca²⁺ release events, and exercise-induced ventricular tachycardia in the CSQ2^–/– murine model of CPVT. Collectively, our studies demonstrate that C11 belongs to an emerging class of allosteric modulators termed PAM-antagonists that positively modulate agonist binding but block downstream function. With unique pharmacological properties and selective functional antagonism of β₁AR-mediated signaling, C11 represents a promising therapeutic candidate for the treatment of CPVT and other forms of cardiac disease associated with excessive β₁AR activation.