7c3g
From Proteopedia
Crystal structure of human ALK2 kinase domain with R206H mutation in complex with a bicyclic pyrazole inhibitor RK-73134
Structural highlights
DiseaseACVR1_HUMAN Fibrodysplasia ossificans progressiva. Defects in ACVR1 are a cause of fibrodysplasia ossificans progressiva (FOP) [MIM:135100. FOP is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification in FOP begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to extra-articular ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible.[1] [2] [3] FunctionACVR1_HUMAN On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity). Publication Abstract from PubMedMutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity. Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.,Yamamoto H, Sakai N, Ohte S, Sato T, Sekimata K, Matsumoto T, Nakamura K, Watanabe H, Mishima-Tsumagari C, Tanaka A, Hashizume Y, Honma T, Katagiri T, Miyazono K, Tomoda H, Shirouzu M, Koyama H Bioorg Med Chem Lett. 2021 Feb 18;38:127858. doi: 10.1016/j.bmcl.2021.127858. PMID:33609658[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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