دورية أكاديمية
أعرض في EDS

Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants.

التفاصيل البيبلوغرافية
العنوان: Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants.
المؤلفون: Mohedas AH; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny GD, Yu PB
المصدر: Journal of medicinal chemistry [J Med Chem] 2014 Oct 09; Vol. 57 (19), pp. 7900-15. Date of Electronic Publication: 2014 Sep 04.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Mutation*, Activin Receptors, Type I/*antagonists & inhibitors , Aminopyridines/*pharmacology , Myositis Ossificans/*drug therapy , Protein Kinase Inhibitors/*pharmacology, Activin Receptors, Type I/genetics ; Aminopyridines/chemical synthesis ; Aminopyridines/metabolism ; Humans ; Myositis Ossificans/genetics ; Phenols/pharmacology ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/metabolism ; Structure-Activity Relationship
مستخلص: There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.
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معلومات مُعتمدة: Canada CAPMC CIHR; United States HHMI Howard Hughes Medical Institute; DK082971-02S1 United States DK NIDDK NIH HHS; 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 Wellcome Trust; AR057374 United States AR NIAMS NIH HHS; R01 DK082971 United States DK NIDDK NIH HHS; AR057374-03S1 United States AR NIAMS NIH HHS; HL079943 United States HL NHLBI NIH HHS
المشرفين على المادة: 0 (3-(6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenol)
0 (Aminopyridines)
0 (Phenols)
0 (Protein Kinase Inhibitors)
EC 2.7.11.30 (ACVR1 protein, human)
EC 2.7.11.30 (Activin Receptors, Type I)
تواريخ الأحداث: Date Created: 20140808 Date Completed: 20141218 Latest Revision: 20211021
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4191596
DOI: 10.1021/jm501177w
PMID: 25101911
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/jm501177w