Discovery and Development of a Novel mPGES-1/5-LOX Dual Inhibitor LFA-9 for Prevention and Treatment of Chronic Inflammatory Diseases.
LFA-9
anti-inflammatory agent
cancer chemoprevention
drug design
mPGES-1/5-LOX dual inhibitor
Journal
Journal of inflammation research
ISSN: 1178-7031
Titre abrégé: J Inflamm Res
Pays: New Zealand
ID NLM: 101512684
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
10
2020
accepted:
01
12
2020
entrez:
7
1
2021
pubmed:
8
1
2021
medline:
8
1
2021
Statut:
epublish
Résumé
Non-steroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 selective inhibitors, have been explored for prevention and treatment of several inflammatory chronic conditions including arthritis, and cancer. However, the long-term use of these drugs is associated with gastrointestinal, renal, and cardiovascular side effects. Later, COX/5-lipoxygenase (5-LOX) dual inhibitors (eg, licofelone) have been developed but did not enter into the market from the clinical trails due to COX-1/2 inhibition-associated side effects. Hence, targeting microsomal prostaglandin E synthase-1 (mPGES-1) and 5-LOX can be an ideal approach while sparing COX-1/2 activities for development of the next generation of anti-inflammatory drugs with better efficacy and safety. In silico (molecular modelling) studies were used to design a mPGES-1/5-LOX dual inhibitory and COX-1/2 sparing lead molecule licofelone analogue-9 (LFA-9) by modifying the pharmacophore of licofelone. In vitro cell-free enzymatic (mPGES-1, 5-LOX, COX-1/2) assays using fluorometric/colorimetric methods and cell-based assays (LPS-induced PGE LFA-9 inhibited mPGES-1/5-LOX and their products PGE Overall study results suggest that LFA-9 is a mPGES-1/5-LOX dual inhibitor and showed anti-inflammatory and colorectal cancer preventive activities, and warranted detailed studies.
Sections du résumé
BACKGROUND
BACKGROUND
Non-steroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 selective inhibitors, have been explored for prevention and treatment of several inflammatory chronic conditions including arthritis, and cancer. However, the long-term use of these drugs is associated with gastrointestinal, renal, and cardiovascular side effects. Later, COX/5-lipoxygenase (5-LOX) dual inhibitors (eg, licofelone) have been developed but did not enter into the market from the clinical trails due to COX-1/2 inhibition-associated side effects. Hence, targeting microsomal prostaglandin E synthase-1 (mPGES-1) and 5-LOX can be an ideal approach while sparing COX-1/2 activities for development of the next generation of anti-inflammatory drugs with better efficacy and safety.
MATERIALS AND METHODS
METHODS
In silico (molecular modelling) studies were used to design a mPGES-1/5-LOX dual inhibitory and COX-1/2 sparing lead molecule licofelone analogue-9 (LFA-9) by modifying the pharmacophore of licofelone. In vitro cell-free enzymatic (mPGES-1, 5-LOX, COX-1/2) assays using fluorometric/colorimetric methods and cell-based assays (LPS-induced PGE
RESULTS
RESULTS
LFA-9 inhibited mPGES-1/5-LOX and their products PGE
CONCLUSION
CONCLUSIONS
Overall study results suggest that LFA-9 is a mPGES-1/5-LOX dual inhibitor and showed anti-inflammatory and colorectal cancer preventive activities, and warranted detailed studies.
Identifiants
pubmed: 33408499
doi: 10.2147/JIR.S286110
pii: 286110
pmc: PMC7781011
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1261-1278Subventions
Organisme : NCI NIH HHS
ID : HHSN261201500024C
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA225520
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213987
Pays : United States
Informations de copyright
© 2020 Yarla et al.
Déclaration de conflit d'intérêts
Gopal Pathuri reports a patent US10206904B2 issued and a patent WO2017/015013 pending. Hariprasad Gali reports a patent US Patent 10206904 issued. Chinthalapally V. Rao reports a patent US10206904B2 issued and a patent WO2017/015013 A1 pending. The authors report no other potential conflicts of interest for this work.
Références
Sci Rep. 2018 Mar 26;8(1):5205
pubmed: 29581541
Science. 2011 Jan 14;331(6014):217-9
pubmed: 21233389
BMB Rep. 2008 Nov 30;41(11):808-13
pubmed: 19017494
PLoS One. 2018 Mar 14;13(3):e0193601
pubmed: 29538403
Ann Rheum Dis. 2003 Jun;62(6):501-9
pubmed: 12759283
Gastroenterology. 2000 Sep;119(3):706-14
pubmed: 10982765
Bioinformatics. 2013 Jul 15;29(14):1750-7
pubmed: 23681122
Future Med Chem. 2017 Aug;9(12):1361-1376
pubmed: 28771028
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3806-11
pubmed: 23431194
J Biol Chem. 2009 Jan 2;284(1):301-5
pubmed: 18984580
Sci Rep. 2017 Aug 16;7(1):8309
pubmed: 28814788
PLoS One. 2015 Aug 25;10(8):e0134472
pubmed: 26305898
Am J Nephrol. 2001 Jan-Feb;21(1):1-15
pubmed: 11275626
Oncogene. 2014 May 15;33(20):2639-54
pubmed: 23752178
Genome Biol. 2004;5(9):241
pubmed: 15345041
Reprod Biomed Online. 2003 Apr-May;6(3):302-9
pubmed: 12735864
Biochem Pharmacol. 2013 Aug 15;86(4):476-86
pubmed: 23623753
J Med Chem. 2010 Apr 8;53(7):2719-40
pubmed: 20131845
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14552-7
pubmed: 19622728
J Med Chem. 2020 Mar 26;63(6):3370-3380
pubmed: 32115956
J Med Chem. 2002 Jun 6;45(12):2615-23
pubmed: 12036371
Anticancer Agents Med Chem. 2015;15(8):1066-77
pubmed: 25642980
J Pharmacol Exp Ther. 2010 Mar;332(3):840-8
pubmed: 19934399
Cancer Prev Res (Phila). 2014 Jul;7(7):708-16
pubmed: 24795386
Prostaglandins Leukot Essent Fatty Acids. 2004 Oct;71(4):233-40
pubmed: 15301794
Adv Exp Med Biol. 2014;816:25-52
pubmed: 24818718
J Pharmacol Exp Ther. 2008 Sep;326(3):975-82
pubmed: 18550688
Endocrinology. 2002 Jun;143(6):2410-9
pubmed: 12021206
Ann Rheum Dis. 2009 Jun;68(6):938-47
pubmed: 18653484
J Med Chem. 2019 Feb 28;62(4):1902-1916
pubmed: 30525602
Drug Metab Lett. 2016;10(2):83-90
pubmed: 26902079
J Med Chem. 2009 Dec 24;52(24):7950-3
pubmed: 19891491
Proteins. 2004 May 1;55(2):288-304
pubmed: 15048822
Am J Cancer Res. 2016 May 01;6(5):894-909
pubmed: 27293987
Cancer Prev Res (Phila). 2011 Dec;4(12):2015-26
pubmed: 21885812
Gastroenterology. 2010 Jun;138(6):2101-2114.e5
pubmed: 20420949
Gastroenterology. 2015 Dec;149(7):1884-1895.e4
pubmed: 26261008
J Med Chem. 2009 Aug 13;52(15):4968-72
pubmed: 19719242
Oncotarget. 2015 Oct 20;6(32):33290-305
pubmed: 26429877
J Biol Chem. 2018 Apr 6;293(14):5295-5306
pubmed: 29440395
Biotechnol Bioeng. 2019 Jan;116(1):206-226
pubmed: 30367820
Biochem J. 2011 Nov 15;440(1):13-21
pubmed: 21797823
Cell Chem Biol. 2019 Jan 17;26(1):9-15
pubmed: 30482678
Cancer Prev Res (Phila). 2015 Apr;8(4):327-37
pubmed: 25657017
Int J Biol Macromol. 2016 Jul;88:624-32
pubmed: 27012893
PLoS One. 2016 Sep 29;11(9):e0163600
pubmed: 27684486
Hypertension. 2007 Mar;49(3):408-18
pubmed: 17261646
Eur J Med Chem. 2018 Jul 15;155:946-960
pubmed: 30015253
J Biol Chem. 2003 Nov 14;278(46):45763-9
pubmed: 12925531
J Pharmacol Exp Ther. 2010 Nov;335(2):443-50
pubmed: 20679133
Pharmacol Res Perspect. 2016 Mar 04;4(2):e00224
pubmed: 27069635