Fibrodysplasia ossificans progressive (FOP) is most commonly caused by a highly recurrent autosomal dominant gain-of-function missense mutation in the ACVR1/ALK2 gene which encodes the activin receptor type Ia[1]. BLU-782 is an oral precision therapy specifically designed to selectively target mutant ALK2 with IC50 value of less than 10 nM[2]. BLU-782 was derived from Blueprint Medicines' proprietary compound library and optimized via structure-guided medicinal chemistry for potent and selective targeting of mutant ALK2. BLU-782 demonstrated exquisite selectivity for R206H mutant ALK2 in cellular assays, while sparing closely related anti-targets including ALK1, ALK3, and ALK6. Additionally, BLU-782 potently inhibited mutant ALK2 in vitro, regardless of the activating ligand, including Activin A, Activin B and BMP6. In vivo studies in a conditional knock-in ALK2R206H transgenic mouse model showed BLU-782 prevented the formation of injury-induced HO and edema, as measured by micro computed tomography and magnetic resonance imaging. In addition, BLU-782 prevented the formation of surgery-induced HO following fibular osteotomy surgery in ALK2R206Hmice[3].
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