Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability.
Animals
Caco-2 Cells
Cell Differentiation
/ drug effects
Dose-Response Relationship, Drug
Female
Humans
Male
Matrix Metalloproteinase 13
Matrix Metalloproteinase Inhibitors
/ chemical synthesis
Mice
Molecular Structure
Osteoclasts
/ drug effects
Osteogenesis
/ drug effects
Solubility
Structure-Activity Relationship
bone metastasis
breast cancer
matrix metalloproteinase
matrix metalloproteinase inhibitor
osteoclastogenesis
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
08 04 2021
08 04 2021
Historique:
revised:
14
12
2020
received:
24
11
2020
pubmed:
18
12
2020
medline:
29
12
2021
entrez:
17
12
2020
Statut:
ppublish
Résumé
Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next-generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis.
Identifiants
pubmed: 33331147
doi: 10.1002/cmdc.202000911
pmc: PMC8035250
mid: NIHMS1665889
doi:
Substances chimiques
Matrix Metalloproteinase Inhibitors
0
MMP13 protein, human
EC 3.4.24.-
Matrix Metalloproteinase 13
EC 3.4.24.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1133-1142Subventions
Organisme : NCI NIH HHS
ID : R01 CA239214
Pays : United States
Organisme : FAU Undergraduate Research Grant
Informations de copyright
© 2020 Wiley-VCH GmbH.
Références
AAPS J. 2006 Jan 13;8(1):E1-13
pubmed: 16584115
Bioorg Med Chem Lett. 2006 Nov 15;16(22):5822-6
pubmed: 16942871
J Med Chem. 2014 Nov 13;57(21):8886-902
pubmed: 25264600
J Med Chem. 2016 Jan 14;59(1):313-27
pubmed: 26653735
BMC Cancer. 2008 Mar 28;8:83
pubmed: 18373849
Biochimie. 2005 Mar-Apr;87(3-4):393-402
pubmed: 15781327
J Biol Chem. 2011 Sep 30;286(39):34271-85
pubmed: 21784845
Cardiovasc Res. 2006 Feb 15;69(3):677-87
pubmed: 16413004
Curr Pharm Biotechnol. 2008 Feb;9(1):47-54
pubmed: 18289056
Bioorg Med Chem Lett. 2005 Apr 1;15(7):1807-10
pubmed: 15780611
Cancer Metastasis Rev. 2014 Dec;33(4):1043-57
pubmed: 25325988
Br J Cancer. 2006 Apr 10;94(7):941-6
pubmed: 16538215
ChemMedChem. 2015 Mar;10(3):451-4
pubmed: 25487909
J Biol Chem. 1994 Jun 17;269(24):16766-73
pubmed: 8207000
Sci Transl Med. 2020 Feb 5;12(529):
pubmed: 32024800
Inflamm Res. 2010 May;59(5):379-89
pubmed: 19902332
Mol Pharmacol. 2008 Jun;73(6):1776-84
pubmed: 18334597
Nat Rev Cancer. 2006 Mar;6(3):227-39
pubmed: 16498445
Ann Rheum Dis. 2010 May;69(5):898-902
pubmed: 19497915
J Med Chem. 2008 Feb 28;51(4):835-41
pubmed: 18251495
J Med Chem. 2012 Jan 26;55(2):709-16
pubmed: 22175799
Bonekey Rep. 2014 Sep 10;3:570
pubmed: 25228983
Clin Orthop Relat Res. 2003 Oct;(415 Suppl):S32-8
pubmed: 14600590
Chem Biol. 2005 Feb;12(2):181-9
pubmed: 15734645
Br J Cancer. 2003 Apr 22;88(8):1318-26
pubmed: 12698202
Bioorg Med Chem Lett. 2009 Sep 15;19(18):5321-4
pubmed: 19692239
Sci Transl Med. 2019 Sep 11;11(509):
pubmed: 31511426
Bioorg Med Chem. 2009 Feb 1;17(3):990-1005
pubmed: 18358729
Cancer Metastasis Rev. 1989 Aug;8(2):98-101
pubmed: 2673568
Semin Cell Dev Biol. 2008 Feb;19(1):61-8
pubmed: 17693104
J Med Chem. 2014 Nov 26;57(22):9598-611
pubmed: 25330343
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
pubmed: 11259830
Breast Cancer Res. 2011 Oct 27;13(5):R105
pubmed: 22032644
Cancer Res. 2010 May 1;70(9):3494-504
pubmed: 20406980
Bioorg Med Chem. 2018 Oct 1;26(18):4984-4995
pubmed: 30249495
Nat Rev Drug Discov. 2003 Mar;2(3):192-204
pubmed: 12612645
ChemistryOpen. 2017 Jan 12;6(2):192-195
pubmed: 28413749
Bioorg Med Chem Lett. 2010 Sep 1;20(17):5039-43
pubmed: 20675133
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10000-5
pubmed: 15220480
ChemMedChem. 2013 Sep;8(9):1457-61, 1572
pubmed: 23894097
Cancers (Basel). 2018 Jun 05;10(6):
pubmed: 29874869
Drug Metab Dispos. 1999 Nov;27(11):1350-9
pubmed: 10534321
PLoS One. 2012;7(1):e29615
pubmed: 22253746
Biopolymers. 2013 Jul;100(4):347-55
pubmed: 23444261
Bioorg Med Chem Lett. 2011 Dec 1;21(23):7180-4
pubmed: 22018790
ChemMedChem. 2017 Aug 8;12(15):1157-1168
pubmed: 28722301
Bioorg Med Chem. 2016 Dec 1;24(23):6149-6165
pubmed: 27825552
Drug Metab Dispos. 2012 Sep;40(9):1803-9
pubmed: 22696420
Oncotarget. 2017 Jun 27;8(26):41827-41840
pubmed: 28611279
Bioorg Med Chem. 2014 Oct 1;22(19):5487-505
pubmed: 25192810
Stem Cell Res Ther. 2016 Sep 09;7(1):129
pubmed: 27612636
Nat Rev Cancer. 2002 Aug;2(8):584-93
pubmed: 12154351
J Biol Chem. 2007 Sep 21;282(38):27781-91
pubmed: 17623656
Genes Dev. 2016 Jan 15;30(2):208-19
pubmed: 26744418
J Med Chem. 2017 Jul 13;60(13):5816-5825
pubmed: 28653849
Arthritis Rheum. 2009 Jul;60(7):2008-18
pubmed: 19565489
Front Biosci. 2006 Jan 01;11:529-43
pubmed: 16146751
Oncol Rep. 2009 Nov;22(5):1119-27
pubmed: 19787229
Curr Opin Drug Discov Devel. 2005 Jul;8(4):495-504
pubmed: 16022186
BMC Cancer. 2019 Jun 14;19(1):581
pubmed: 31200666
Mol Pharm. 2017 May 1;14(5):1601-1609
pubmed: 28329446
J Med Chem. 2001 Apr 26;44(9):1313-33
pubmed: 11311053