Discovery of BGM1812, a Novel Dual Amylin and Calcitonin Receptor Agonist for Obesity Treatment.

Parallel activation of the calcitonin receptor (CTR) and amylin receptor (AMYR) is considered a more effective weight-loss strategy. Although the novel dual amylin and calcitonin receptor agonist (DACRA), petrelintide, is currently undergoing phase II clinical trials, its agonistic activity remains insufficient compared with natural agonists. Further optimization of the agonistic capabilities of petrelintide is an attractive strategy for developing DACRAs. Due to the lack of structure-activity relationship (SAR) and target binding information, a step-by-step process involving three rounds of modifications was performed guided by structure-based drug design and molecular dynamics (MD) simulations. Two successful methylation strategies led to the identification of the more efficient novel DACRA, BGM1812, with excellent performance in terms of half-life, stability, and solubility. In both in vivo and in vitro studies, BGM1812 showed significantly enhanced efficacy. This finding provides valuable insights into the SAR of petrelintide and highlights the potential of BGM1812 as a promising obesity drug candidate.