Novel β1AR Allosteric Modulator Discovered from OpenDEL™ Shows Promise in Treating Cardiac Arrhythmia Release Time：2025-11-13

A groundbreaking study from Duke University, led by Nobel Laureate Professor Robert J. Lefkowitz and Professor Howard A. Rockman, has identified a novel allosteric modulator of the β1-adrenergic receptor (β1AR) with a unique "PAM-antagonist" mechanism. The research, published in The Journal of Clinical Investigation, utilized HitGen OpenDEL™ and demonstrated significant potential for treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a life-threatening cardiac arrhythmia (Fig.1).

Fig.1. JCI Graphical Abstract

Key Research Findings:

·  Unique Dual Mechanism: The lead compound, C11 (Fig. 2), functions as a PAM-antagonist – enhancing agonist binding affinity to β1AR while potently inhibiting downstream G protein and β-arrestin signaling pathways.

· Therapeutic Efficacy: In preclinical models, C11 effectively suppressed spontaneous calcium release, arrhythmic contractions in cardiomyocytes, and exercise-induced ventricular tachycardia.

· Advantage over Traditional Therapies: This approach may offer superior subtype selectivity compared to conventional orthosteric beta-blockers, potentially reducing side effects like hypotension and fatigue.

Fig.2. Schematic of the chemical structure 902 of C11

Role of OpenDEL™:

The initial discovery of C11 was made through affinity screening of HitGen OpenDEL™ (Fig.3), demonstrating the value of DNA-encoded library technology in identifying novel allosteric modulators for challenging GPCR targets. The library's diverse collection of over one billion compounds provided the essential chemical space for this breakthrough discovery.

Fig.3. Affinity Selection Process for C11 Discovery with OpenDEL™

About OpenDEL™

In 2015, HitGen officially launched OpenDEL™, a self-service DEL screening product. Through continuous upgrades, OpenDEL™ now contains approximately 4 billion compounds across 59 DNA-encoded libraries, with macrocyclic libraries available as an optional addition to meet diverse screening needs.

Beyond the OpenDEL™, HitGen also offers end-to-end services including screening, sequencing, and hit optimization, while ensuring full protection of clients’ intellectual property. This integrated approach accelerates drug discovery projects with flexibility and confidence.