Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
22 09 2022
22 09 2022
Historique:
received:
14
09
2021
accepted:
02
09
2022
entrez:
22
9
2022
pubmed:
23
9
2022
medline:
28
9
2022
Statut:
epublish
Résumé
Oncogenic RAS proteins are important for driving tumour formation, and for maintenance of the transformed phenotype, and thus their relevance as a cancer therapeutic target is undeniable. We focused here on obtaining peptidomimetics, which have good pharmacological properties, to block Ras-effector interaction. Computational analysis was used to identify hot spots of RAS relevant for these interactions and to screen a library of peptidomimetics. Nine compounds were synthesized and assayed for their activity as RAS inhibitors in cultured cells. Most of them induced a reduction in ERK and AKT activation by EGF, a marker of RAS activity. The most potent inhibitor disrupted Raf and PI3K interaction with oncogenic KRAS, corroborating its mechanism of action as an inhibitor of protein-protein interactions, and thus validating our computational methodology. Most interestingly, improvement of one of the compounds allowed us to obtain a peptidomimetic that decreased the survival of pancreatic cancer cell lines harbouring oncogenic KRAS.
Identifiants
pubmed: 36138080
doi: 10.1038/s41598-022-19703-6
pii: 10.1038/s41598-022-19703-6
pmc: PMC9499927
doi:
Substances chimiques
Peptidomimetics
0
Epidermal Growth Factor
62229-50-9
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15810Informations de copyright
© 2022. The Author(s).
Références
Pept Res. 1995 Jul-Aug;8(4):236-7
pubmed: 8527877
J Biol Chem. 2008 Apr 18;283(16):10621-31
pubmed: 18182391
Nat Rev Cancer. 2003 Jun;3(6):459-65
pubmed: 12778136
J Comput Chem. 2009 Dec;30(16):2785-91
pubmed: 19399780
Trends Biochem Sci. 2006 Feb;31(2):76-8
pubmed: 16406633
Nature. 2019 Nov;575(7781):217-223
pubmed: 31666701
Cell. 2016 Apr 21;165(3):643-55
pubmed: 27104980
Biochem J. 2019 Jan 31;476(2):365-374
pubmed: 30705085
Nat Med. 2013 Aug;19(8):949-50
pubmed: 23921727
Med Chem. 2011 Mar;7(2):121-6
pubmed: 21222611
Nat Rev Cancer. 2011 Oct 13;11(11):761-74
pubmed: 21993244
Ann Oncol. 2015 Sep;26(9):1923-1929
pubmed: 26091808
J Comput Chem. 2005 Dec;26(16):1668-88
pubmed: 16200636
Oncogene. 2010 Nov 11;29(45):6064-70
pubmed: 20818422
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Curr Pharm Biotechnol. 2008 Apr;9(2):103-22
pubmed: 18393867
EMBO J. 1990 Aug;9(8):2351-9
pubmed: 2196171
Sci Signal. 2018 Oct 30;11(554):
pubmed: 30377222
Science. 2017 Mar 17;355(6330):1158-1163
pubmed: 28302824
Cancer Res. 2017 Jan 15;77(2):221-226
pubmed: 28062402
Nature. 1999 Jul 29;400(6743):468-72
pubmed: 10440378
Cancer Cell. 2018 Feb 12;33(2):158-159
pubmed: 29438690
PLoS One. 2016 Dec 9;11(12):e0167145
pubmed: 27936046
J Mol Biol. 1963 Jul;7:95-9
pubmed: 13990617
Crit Rev Oncol Hematol. 2018 Oct;130:78-91
pubmed: 30196915
Cancer Cell. 2002 Sep;2(3):243-7
pubmed: 12242156
Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31
pubmed: 18568040
Nat Chem Biol. 2017 Jan;13(1):62-68
pubmed: 27820802
J Comput Chem. 2005 Dec;26(16):1781-802
pubmed: 16222654
Nature. 1991 Jan 10;349(6305):117-27
pubmed: 1898771
PLoS Comput Biol. 2010 Jun 24;6(6):e1000807
pubmed: 20589078
J Clin Invest. 2012 Feb;122(2):639-53
pubmed: 22232209
J Biol Chem. 2002 Oct 4;277(40):37929-35
pubmed: 12151388
Cell. 2017 Feb 23;168(5):878-889.e29
pubmed: 28235199
Mol Biol Cell. 2019 Apr 15;30(9):1108-1117
pubmed: 30785867
Cell Cycle. 2009 Sep 1;8(17):2676-7
pubmed: 19690457
Acc Chem Res. 2017 Aug 15;50(8):1847-1854
pubmed: 28715199
Pharmacol Res. 2019 Jan;139:503-511
pubmed: 30366101
Curr Opin Cell Biol. 1996 Apr;8(2):197-204
pubmed: 8791426
Genes (Basel). 2021 Apr 28;12(5):
pubmed: 33924994
Curr Med Chem. 2009;16(1):21-41
pubmed: 19149561
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
Cancer Discov. 2020 Jan;10(1):54-71
pubmed: 31658955
Chem Soc Rev. 2016 Sep 21;45(18):4929-52
pubmed: 27396271
Anal Biochem. 1970 Apr;34(2):595-8
pubmed: 5443684
Nat Cancer. 2020 Jan;1(1):25-27
pubmed: 35121842
Nat Commun. 2021 May 11;12(1):2656
pubmed: 33976200
J Mol Med (Berl). 2016 Mar;94(3):253-8
pubmed: 26960760
Cancer Res. 2012 May 15;72(10):2457-67
pubmed: 22589270
Cell Rep. 2018 Feb 13;22(7):1889-1902
pubmed: 29444439
ACS Comb Sci. 2016 Jan 11;18(1):75-85
pubmed: 26645887
Cell. 1989 Jun 30;57(7):1167-77
pubmed: 2661017
Cancer Cell. 2014 Mar 17;25(3):272-81
pubmed: 24651010
Cell. 2007 Jun 1;129(5):865-77
pubmed: 17540168
J Chem Inf Model. 2016 Jan 25;56(1):188-200
pubmed: 26651532
Oncol Lett. 2018 Jul;16(1):632-642
pubmed: 29928450
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W537-41
pubmed: 22570416
Med Chem. 2011 Jan;7(1):24-31
pubmed: 21235516
Cell Mol Life Sci. 2016 Dec;73(23):4397-4413
pubmed: 27342992
Curr Opin Chem Biol. 2017 Jun;38:80-86
pubmed: 28388463
Cell. 2012 Apr 27;149(3):656-70
pubmed: 22541435
Org Lett. 2018 Sep 21;20(18):5737-5742
pubmed: 30207734
Genes Dev. 2001 Dec 15;15(24):3249-62
pubmed: 11751631
EMBO J. 2010 Mar 17;29(6):1091-104
pubmed: 20150892
Cancer Res. 2020 Jul 15;80(14):2969-2974
pubmed: 32209560