دورية أكاديمية
أعرض في EDS

A new class of small molecule inhibitor of BMP signaling.

التفاصيل البيبلوغرافية
العنوان: A new class of small molecule inhibitor of BMP signaling.
المؤلفون: Sanvitale CE; Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom., Kerr G, Chaikuad A, Ramel MC, Mohedas AH, Reichert S, Wang Y, Triffitt JT, Cuny GD, Yu PB, Hill CS, Bullock AN
المصدر: PloS one [PLoS One] 2013 Apr 30; Vol. 8 (4), pp. e62721. Date of Electronic Publication: 2013 Apr 30 (Print Publication: 2013).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science
مواضيع طبية MeSH: Aminopyridines/*pharmacology , Bone Morphogenetic Proteins/*antagonists & inhibitors , Phenols/*pharmacology , Signal Transduction/*drug effects, Activin Receptors, Type I/antagonists & inhibitors ; Activin Receptors, Type I/chemistry ; Aminopyridines/chemistry ; Animals ; Body Patterning/drug effects ; Bone Morphogenetic Proteins/chemistry ; Bone Morphogenetic Proteins/metabolism ; Humans ; Models, Molecular ; Molecular Conformation ; Neovascularization, Physiologic/drug effects ; Phenols/chemistry ; Protein Binding ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Smad Proteins/metabolism ; Zebrafish
مستخلص: Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.
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معلومات مُعتمدة: 15681 United Kingdom CRUK_ Cancer Research UK; Canada CAPMC CIHR; R01 AR057374 United States AR NIAMS NIH HHS; 092809/Z/10/Z United Kingdom WT_ Wellcome Trust; K08 HL079943 United States HL NHLBI NIH HHS; 092809 United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust; AR057374 United States AR NIAMS NIH HHS
المشرفين على المادة: 0 (3-(6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenol)
0 (Aminopyridines)
0 (Bone Morphogenetic Proteins)
0 (LDN 193189)
0 (Phenols)
0 (Protein Kinase Inhibitors)
0 (Pyrazoles)
0 (Pyrimidines)
0 (Smad Proteins)
EC 2.7.11.30 (ACVR1 protein, human)
EC 2.7.11.30 (Activin Receptors, Type I)
WSX981HEWU (alpha-aminopyridine)
تواريخ الأحداث: Date Created: 20130507 Date Completed: 20131126 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC3639963
DOI: 10.1371/journal.pone.0062721
PMID: 23646137
قاعدة البيانات: MEDLINE
الوصف
تدمد:1932-6203
DOI:10.1371/journal.pone.0062721