A novel binding pocket in the D2 domain of protein tyrosine phosphatase mu (PTPmu) guides AI screen to identify small molecules that modulate tumour cell adhesion, growth and migration.
artificial intelligence
cell adhesion
cell-cell adhesion
drug design
glioblastoma
glioma
protein tyrosine phosphatase mu
receptor protein tyrosine phosphatase
tyrosine phosphatase
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
revised:
25
08
2023
received:
19
02
2023
accepted:
16
09
2023
medline:
22
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
Approximately 40% of people will get cancer in their lifetime in the US, and 20% are predicted to die from the condition when it is invasive and metastatic. Targeted screening for drugs that interact with proteins that drive cancer cell growth and migration can lead to new therapies. We screened molecular libraries with the AtomNet® AI-based drug design tool to identify compounds predicted to interact with the cytoplasmic domain of protein tyrosine phosphatase mu. Protein tyrosine phosphatase mu (PTPmu) is proteolytically downregulated in cancers such as glioblastoma generating fragments that stimulate cell survival and migration. Aberrant nuclear localization of PTPmu intracellular fragments drives cancer progression, so we targeted a predicted drug-binding site between the two cytoplasmic phosphatase domains we termed a D2 binding pocket. The function of the D2 domain is controversial with various proposed regulatory functions, making the D2 domain an attractive target for the development of allosteric drugs. Seventy-five of the best-scoring and chemically diverse computational hits predicted to interact with the D2 binding pocket were screened for effects on tumour cell motility and growth in 3D culture as well as in a direct assay for PTPmu-dependent adhesion. We identified two high-priority hits that inhibited the migration and glioma cell sphere formation of multiple glioma tumour cell lines as well as aggregation. We also identified one activator of PTPmu-dependent aggregation, which was able to stimulate cell migration. We propose that the PTPmu D2 binding pocket represents a novel regulatory site and that inhibitors targeting this region may have therapeutic potential for treating cancer.
Identifiants
pubmed: 37860940
doi: 10.1111/jcmm.17973
pmc: PMC10660673
doi:
Substances chimiques
Receptor-Like Protein Tyrosine Phosphatases, Class 2
EC 3.1.3.48
Protein Tyrosine Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3553-3564Subventions
Organisme : Atomwise
ID : A17-020
Informations de copyright
© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Références
J Cell Biol. 1995 Aug;130(4):977-86
pubmed: 7642713
Dev Biol. 2004 Nov 1;275(1):12-22
pubmed: 15464569
Cell Commun Adhes. 2010 Apr;17(2):34-47
pubmed: 20521994
Neuro Oncol. 2009 Dec;11(6):767-78
pubmed: 19304959
J Biol Chem. 2006 Jun 16;281(24):16482-92
pubmed: 16613844
EMBO J. 1990 Aug;9(8):2399-407
pubmed: 1695146
Nature. 1996 Aug 8;382(6591):555-9
pubmed: 8700232
Mol Pharmacol. 2014 Apr;85(4):553-63
pubmed: 24473749
J Biol Chem. 1997 Oct 31;272(44):27505-8
pubmed: 9346878
J Neurosci. 2002 May 1;22(9):3615-27
pubmed: 11978837
Mol Cell Neurosci. 2004 Apr;25(4):558-71
pubmed: 15080886
Mol Cell Biochem. 1993 Nov;127-128:131-41
pubmed: 7935345
Int J Mol Sci. 2023 Feb 21;24(5):
pubmed: 36901713
Nat Rev Cancer. 2011 Jan;11(1):35-49
pubmed: 21179176
Nat Rev Drug Discov. 2021 Jul;20(7):551-569
pubmed: 34002056
Oncol Rep. 2015 Apr;33(4):1837-43
pubmed: 25634491
Diagnostics (Basel). 2021 Jan 27;11(2):
pubmed: 33513911
Cancer Res. 2011 Sep 1;71(17):5932-40
pubmed: 21862632
J Biol Chem. 2000 May 19;275(20):15350-6
pubmed: 10809770
Neurosci Lett. 2021 Aug 24;760:136079
pubmed: 34166723
Acta Crystallogr D Struct Biol. 2018 Oct 1;74(Pt 10):1015-1026
pubmed: 30289412
Trends Pharmacol Sci. 2017 Jun;38(6):524-540
pubmed: 28412041
Adv Sci (Weinh). 2021 Jul;8(14):e2004846
pubmed: 34060252
Med Res Rev. 2022 May;42(3):1064-1110
pubmed: 34791703
J Cell Mol Med. 2023 Nov;27(22):3553-3564
pubmed: 37860940
Neuropharmacology. 2019 Jan;144:208-218
pubmed: 30393073
Cell. 2009 Jan 23;136(2):352-63
pubmed: 19167335
PLoS One. 2023 Jul 26;18(7):e0288980
pubmed: 37494327
J Biol Chem. 2020 Apr 10;295(15):4923-4936
pubmed: 32139509
Mol Cell Neurosci. 2007 Mar;34(3):481-92
pubmed: 17276081
Nature. 2015 Feb 19;518(7539):404-8
pubmed: 25470046
J Cell Biol. 1999 Mar 22;144(6):1323-36
pubmed: 10087273
J Cell Biol. 1993 Aug;122(4):961-72
pubmed: 8394372
Mol Cell Biol. 1998 May;18(5):2608-16
pubmed: 9566880
Cancer Res. 2009 Sep 1;69(17):6960-8
pubmed: 19690139
Cancer Res. 2011 Jan 15;71(2):303-9
pubmed: 21084269
EMBO J. 1991 Nov;10(11):3231-7
pubmed: 1915292
J Biol Chem. 1998 Jul 10;273(28):17839-45
pubmed: 9651387
Acc Chem Res. 2017 Jan 17;50(1):122-129
pubmed: 27977138
J Biomed Mater Res B Appl Biomater. 2021 Nov;109(11):1744-1753
pubmed: 33847464
Anticancer Agents Med Chem. 2011 Jan;11(1):133-40
pubmed: 21235433
Cell. 1999 May 14;97(4):449-57
pubmed: 10338209
J Cell Biochem. 2011 Jan;112(1):39-48
pubmed: 20506511
Biochem Biophys Res Commun. 1995 Jan 5;206(1):302-9
pubmed: 7818534
Cell Adh Migr. 2011 Jul-Aug;5(4):298-305
pubmed: 21785275
Semin Cell Dev Biol. 2015 Jan;37:108-18
pubmed: 25223585
Mol Cell Biol. 2000 Aug;20(16):5917-29
pubmed: 10913175
Neoplasia. 2002 Nov-Dec;4(6):523-30
pubmed: 12407446
J Biol Chem. 2019 Oct 11;294(41):14953-14965
pubmed: 31416834
J Struct Funct Genomics. 2007 Sep;8(2-3):121-40
pubmed: 18058037
J Biol Chem. 2002 Mar 29;277(13):11165-73
pubmed: 11801604
Mol Cell Neurosci. 2005 Jan;28(1):177-88
pubmed: 15607952
BMC Cell Biol. 2001;2:8
pubmed: 11401727