Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
12 08 2021
12 08 2021
Historique:
pubmed:
16
7
2021
medline:
21
10
2021
entrez:
15
7
2021
Statut:
ppublish
Résumé
CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency
Identifiants
pubmed: 34264658
doi: 10.1021/acs.jmedchem.0c02274
pmc: PMC8365604
doi:
Substances chimiques
Calmodulin
0
Protein Kinase Inhibitors
0
CAMKK2 protein, human
EC 2.7.11.17
Calcium-Calmodulin-Dependent Protein Kinase Kinase
EC 2.7.11.17
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
10849-10877Subventions
Organisme : NCI NIH HHS
ID : R01 CA184208
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK116204
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218442
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR029205
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103403
Pays : United States
Références
Cancer Res. 2008 Sep 15;68(18):7475-83
pubmed: 18794135
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
pubmed: 21460454
Tumour Biol. 2015 Mar;36(3):1983-91
pubmed: 25394900
J Biol Chem. 2012 Jul 13;287(29):24832-43
pubmed: 22654108
J Biol Chem. 2003 Mar 28;278(13):10908-13
pubmed: 12540834
CNS Neurosci Ther. 2016 Jun;22(6):518-24
pubmed: 27012733
J Biol Chem. 1998 Nov 27;273(48):31880-9
pubmed: 9822657
Am J Transl Res. 2016 Feb 15;8(2):1164-71
pubmed: 27158402
J Biol Chem. 2012 Sep 14;287(38):31658-65
pubmed: 22778263
Oncotarget. 2014 Nov 15;5(21):10840-53
pubmed: 25333262
J Med Chem. 2015 Jun 11;58(11):4383-438
pubmed: 25734370
Sci Rep. 2018 Oct 4;8(1):14800
pubmed: 30287839
Adv Drug Deliv Rev. 2007 Jul 30;59(7):546-67
pubmed: 17604872
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Bioorg Med Chem Lett. 2018 Jun 1;28(10):1958-1963
pubmed: 29653895
Chem Pharm Bull (Tokyo). 2018;66(1):29-36
pubmed: 29311509
Cell. 2007 Dec 14;131(6):1047-58
pubmed: 18083096
Mol Cell Biochem. 2010 Feb;335(1-2):155-71
pubmed: 19763792
Oncogene. 2001 May 31;20(25):3247-57
pubmed: 11423974
Cancer Res. 2011 Jan 15;71(2):528-37
pubmed: 21098087
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Nature. 1998 Dec 10;396(6711):584-7
pubmed: 9859994
EMBO J. 2011 May 20;30(13):2719-33
pubmed: 21602788
Drug Discov Today. 2010 Aug;15(15-16):648-55
pubmed: 20570751
Annu Rev Pharmacol Toxicol. 2001;41:471-505
pubmed: 11264466
Drug Discov Today. 2018 Mar;23(3):605-615
pubmed: 29330127
J Biol Chem. 2017 Aug 25;292(34):14188-14204
pubmed: 28634229
J Chem Inf Model. 2015 Oct 26;55(10):2138-53
pubmed: 26393532
Eur J Pharm Sci. 2012 Oct 9;47(3):589-95
pubmed: 22885099
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
pubmed: 11259830
Cell Signal. 2011 Dec;23(12):2005-12
pubmed: 21807092
Cell Chem Biol. 2018 Feb 15;25(2):206-214.e11
pubmed: 29174542
Bipolar Disord. 2020 Dec;22(8):841-848
pubmed: 32216002
Hepatology. 2015 Aug;62(2):505-20
pubmed: 25847065
Sci Rep. 2019 Nov 11;9(1):16452
pubmed: 31712618
J Bone Miner Res. 2013 Jul;28(7):1599-610
pubmed: 23408651
J Biol Chem. 2011 Jun 24;286(25):22570-9
pubmed: 21504895
Nat Protoc. 2007;2(9):2212-21
pubmed: 17853878
Nat Biotechnol. 2011 Oct 30;29(11):1046-51
pubmed: 22037378
Cell Calcium. 2018 Nov;75:89-100
pubmed: 30205293
J Med Chem. 2004 Nov 4;47(23):5616-9
pubmed: 15509160
Trends Cell Biol. 2000 Aug;10(8):322-8
pubmed: 10884684
Cancer Res. 2005 Jun 15;65(12):5408-16
pubmed: 15958590
Acta Crystallogr D Biol Crystallogr. 2004 Mar;60(Pt 3):610-2
pubmed: 14993709
Sci Rep. 2017 Sep 18;7(1):11793
pubmed: 28924233
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
J Med Chem. 2008 Sep 11;51(17):5149-71
pubmed: 18710211
Cancer Biol Ther. 2015;16(2):336-45
pubmed: 25756516
Molecules. 2020 Jan 13;25(2):
pubmed: 31941153
Nat Rev Drug Discov. 2014 Feb;13(2):105-21
pubmed: 24481311
PLoS One. 2016 Apr 06;11(4):e0152856
pubmed: 27049755
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Drug Metab Dispos. 2008 Dec;36(12):2556-63
pubmed: 18755850
Molecules. 2018 May 19;23(5):
pubmed: 29783765
Cell Metab. 2005 Jul;2(1):9-19
pubmed: 16054095
J Biol Chem. 2020 Nov 27;295(48):16239-16250
pubmed: 32913128
Clin Gastroenterol Hepatol. 2011 May;9(5):428-33; quiz e50
pubmed: 21320639
World J Gastroenterol. 2010 Mar 28;16(12):1436-41
pubmed: 20333782
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Methods Mol Biol. 2012;795:109-18
pubmed: 21960218
J Biol Chem. 2002 May 3;277(18):15813-8
pubmed: 11867640
J Hematol Oncol. 2018 Feb 27;11(1):30
pubmed: 29482582
Biochem J. 2020 Sep 18;477(17):3453-3469
pubmed: 32869834
Bioorg Med Chem. 2015 Oct 1;23(19):6520-7
pubmed: 26358279
Prostate. 2012 Dec 1;72(16):1789-801
pubmed: 22549914
J Med Chem. 2004 Mar 25;47(7):1750-9
pubmed: 15027866
Cell Metab. 2008 May;7(5):377-88
pubmed: 18460329
Bone. 2015 Jun;75:120-7
pubmed: 25724145
Endocrinology. 2011 Oct;152(10):3668-79
pubmed: 21862616
Endocr Relat Cancer. 2018 Apr;25(4):453-469
pubmed: 29431615