6gi6
Crystal structure of the ACVR1 (ALK2) kinase in complex with a Quinazolinone based ALK2 inhibitor with a 5-methyl core.Crystal structure of the ACVR1 (ALK2) kinase in complex with a Quinazolinone based ALK2 inhibitor with a 5-methyl core.
Structural highlights
Disease[ACVR1_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] Function[ACVR1_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 PubMedStructure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors. Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.,Hudson L, Mui J, Vazquez S, Carvalho DM, Williams E, Jones C, Bullock AN, Hoelder S J Med Chem. 2018 Aug 7. doi: 10.1021/acs.jmedchem.8b00782. PMID:30085668[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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