Structure-Activity Relationship Analysis of Rhosin, a RhoA GTPase Inhibitor, Reveals a New Class of Antiplatelet Agents.
Rho GTPase signaling
antiplatelet
chiral enantiomer
hemostasis
platelet activation
small-molecule inhibitor
thrombosis
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
19 Feb 2023
19 Feb 2023
Historique:
received:
23
01
2023
revised:
14
02
2023
accepted:
17
02
2023
entrez:
25
2
2023
pubmed:
26
2
2023
medline:
3
3
2023
Statut:
epublish
Résumé
Current antiplatelet therapies have several clinical complications and are mostly irreversible in terms of suppressing platelet activity; hence, there is a need to develop improved therapeutic agents. Previous studies have implicated RhoA in platelet activation. Here, we further characterized the lead RhoA inhibitor, Rhosin/G04, in platelet function and present structure-activity relationship (SAR) analysis. A screening for Rhosin/G04 analogs in our chemical library by similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. A screening for Rhosin/G04 analogs in our chemical library using similarity and substructure searches revealed compounds that showed enhanced antiplatelet activity and suppressed RhoA activity and signaling. SAR analysis revealed that the active compounds have a quinoline group optimally attached to the hydrazine at the 4-position and halogen substituents at the 7- or 8-position. Having indole, methylphenyl, or dichloro-phenyl substituents led to better potency. Rhosin/G04 contains a pair of enantiomers, and S-G04 is significantly more potent than R-G04 in inhibiting RhoA activation and platelet aggregation. Furthermore, the inhibitory effect is reversible, and S-G04 is capable of inhibiting diverse-agonist-stimulated platelet activation. This study identified a new generation of small-molecule RhoA inhibitors, including an enantiomer capable of broadly and reversibly modulating platelet activity.
Identifiants
pubmed: 36835579
pii: ijms24044167
doi: 10.3390/ijms24044167
pmc: PMC9961652
pii:
doi:
Substances chimiques
Platelet Aggregation Inhibitors
0
rhosin
0
rhoA GTP-Binding Protein
EC 3.6.5.2
Organic Chemicals
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL158688
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK126108
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204895
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147536
Pays : United States
Organisme : NIH HHS
ID : U54 DK126108, R01 CA204895, R01 HL147536.
Pays : United States
Références
Physiol Rev. 2013 Jan;93(1):327-58
pubmed: 23303912
J Transl Med. 2010 Dec 06;8:128
pubmed: 21134286
Chem Biol. 2012 Jun 22;19(6):699-710
pubmed: 22726684
J Neurol Neurosurg Psychiatry. 1971 Dec;34(6):682-6
pubmed: 5158783
Phytother Res. 2008 Jan;22(1):58-64
pubmed: 17724769
Bioorg Med Chem. 2003 May 1;11(9):2051-9
pubmed: 12670656
Proc Natl Acad Sci U S A. 1975 Aug;72(8):2994-8
pubmed: 1059088
Br J Clin Pharmacol. 1992 Jan;33(1):25-31
pubmed: 1540486
Eur J Med Chem. 2008 Feb;43(2):348-56
pubmed: 17532545
Open Heart. 2017 Oct 15;4(2):e000651
pubmed: 29081979
Eur J Pharm Sci. 2000 Oct;11(4):285-90
pubmed: 11033071
Curr Opin Cell Biol. 2012 Oct;24(5):600-6
pubmed: 22980731
PLoS One. 2011;6(7):e22117
pubmed: 21789221
Circ Res. 2006 Dec 8;99(12):1293-304
pubmed: 17158345
Circulation. 2011 Feb 22;123(7):768-78
pubmed: 21343593
Methods Enzymol. 2006;406:554-65
pubmed: 16472687
Molecules. 2014 Feb 17;19(2):2089-99
pubmed: 24549233
Int J Endocrinol. 2011;2011:742719
pubmed: 21869886
Ann N Y Acad Sci. 1972 Oct 27;201:22-36
pubmed: 4346061
J Thromb Haemost. 2018 Oct;16(10):2083-2096
pubmed: 30007118
Chest. 2012 Feb;141(2 Suppl):e89S-e119S
pubmed: 22315278
Chem Pharm Bull (Tokyo). 2013;61(2):160-6
pubmed: 23183543
J Cell Biol. 1999 Feb 22;144(4):745-54
pubmed: 10037795
Blood. 2009 Jul 9;114(2):415-24
pubmed: 19429871
Thromb Haemost. 2011 Nov;106(5):827-38
pubmed: 22012554
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
pubmed: 10592235
J Biol Chem. 2004 Nov 5;279(45):47352-62
pubmed: 15331592
Chem Pharm Bull (Tokyo). 2013;61(2):144-50
pubmed: 23154304
Ann Rheum Dis. 1977 Oct;36(5):459-63
pubmed: 411427
J Biol Chem. 2001 May 18;276(20):17036-43
pubmed: 11278299
Nature. 1962 Jun 9;194:927-9
pubmed: 13871375
Clin Med (Lond). 2016 Apr;16(2):152-60
pubmed: 27037385
Chem Cent J. 2018 Feb 7;12(1):11
pubmed: 29411174
PLoS One. 2016 Sep 28;11(9):e0163227
pubmed: 27681226
Eur J Med Chem. 2020 Apr 15;192:112187
pubmed: 32155530
Br J Haematol. 1976 Sep;34(1):137-46
pubmed: 952763
Methods Mol Biol. 2012;928:29-38
pubmed: 22956131
Clin Chim Acta. 1966 Apr;13(4):431-4
pubmed: 5927334
J Thromb Thrombolysis. 2012 Jul;34(1):44-55
pubmed: 22569899
Sci Rep. 2018 Jun 22;8(1):9528
pubmed: 29934595
Br J Pharmacol. 1995 May;115(1):101-6
pubmed: 7647963
Res Pharm Sci. 2021 Nov 11;17(1):53-65
pubmed: 34909044
Iran J Pharm Res. 2014 Winter;13(Suppl):35-42
pubmed: 24711827
Expert Rev Cardiovasc Ther. 2009 Oct;7(10):1195-201
pubmed: 19814662
Eur J Pharmacol. 2010 Jul 25;638(1-3):5-12
pubmed: 20412790
J Chem Inf Model. 2015 Nov 23;55(11):2324-37
pubmed: 26479676
Biochem J. 1989 Feb 15;258(1):157-63
pubmed: 2539100
Infect Immun. 1981 Aug;33(2):467-72
pubmed: 7275312
Hypertension. 2003 Feb;41(2):199-200
pubmed: 12574081
Ann Med. 2011 Nov;43(7):531-44
pubmed: 21815879
Proc Natl Acad Sci U S A. 1986 Aug;83(16):5861-5
pubmed: 3461463
Fed Proc. 1987 Jan;46(1):154-8
pubmed: 3100340
Blood. 2012 Jan 26;119(4):1054-63
pubmed: 22045984
Exp Mol Med. 2005 Dec 31;37(6):575-87
pubmed: 16391519
Nat Struct Biol. 1997 Sep;4(9):699-703
pubmed: 9302995
Blood. 2009 Jan 22;113(4):893-901
pubmed: 18957688
J Thromb Haemost. 2007 Aug;5(8):1747-55
pubmed: 17663742
Am J Cardiol. 2009 Feb 2;103(3 Suppl):27A-34A
pubmed: 19166710