1区 · 医学
Article
作者: Macina, Justyna ; McCormick, Patricia ; Biddulph, Ross ; Cecconie, Ted ; Macphee, Colin ; Rauch, Martin ; Buxton, Rachel ; Stebbeds, Will ; Gao, Enoch N. ; Wang, Xin ; Brady, Jennifer J. ; Lawler, Meghan ; Bedermann, Aaron ; Lian, Yiqian ; Bingham, Ryan ; Martin, John ; Ward, Paris ; Andrews, Logan ; Pindoria, Rekha ; Marcaurelle, Lisa ; Shen, Yingnian ; Tear, Westley ; Xiao, Shouhua ; Squire, Michael ; Rocque, Warren ; Shewchuk, Lisa M. ; Csakai, Adam ; Yao, Gang ; Grenier-Davies, Melissa C. ; Cooper, Rona ; Rowley, Ann M.
Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.
