Parallel Automated Flow Synthesis of Covalent Protein Complexes That Can Inhibit MYC-Driven Transcription.
Journal
ACS central science
ISSN: 2374-7943
Titre abrégé: ACS Cent Sci
Pays: United States
ID NLM: 101660035
Informations de publication
Date de publication:
25 Aug 2021
25 Aug 2021
Historique:
received:
01
06
2021
entrez:
2
9
2021
pubmed:
3
9
2021
medline:
3
9
2021
Statut:
ppublish
Résumé
Dysregulation of the transcription factor MYC is involved in many human cancers. The dimeric transcription factor complexes of MYC/MAX and MAX/MAX activate or inhibit, respectively, gene transcription upon binding to the same enhancer box DNA. Targeting these complexes in cancer is a long-standing challenge. Inspired by the inhibitory activity of the MAX/MAX dimer, we engineered covalently linked, synthetic homo- and heterodimeric protein complexes to attenuate oncogenic MYC-driven transcription. We prepared the covalent protein complexes (∼20 kDa, 167-231 residues) in a single shot via parallel automated flow synthesis in hours. The stabilized covalent dimers display DNA binding activity, are intrinsically cell-penetrant, and inhibit cancer cell proliferation in different cell lines. RNA sequencing and gene set enrichment analysis in A549 cancer cells confirmed that the synthetic dimers interfere with MYC-driven transcription. Our results demonstrate the potential of automated flow technology to rapidly deliver engineered synthetic protein complex mimetics that can serve as a starting point in developing inhibitors of MYC-driven cancer cell growth.
Identifiants
pubmed: 34471684
doi: 10.1021/acscentsci.1c00663
pmc: PMC8393199
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1408-1418Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM087237
Pays : United States
Informations de copyright
© 2021 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): B.L.P. is a cofounder of Amide Technologies and Resolute Bio. Both companies focus on the development of protein and peptide therapeutics. MIT is in the process of filing a provisional patent application regarding the compounds described in this study. A.B. is an advisor to Syros Pharmaceuticals.
Références
Cell Chem Biol. 2021 Jan 21;28(1):4-13.e17
pubmed: 32966806
Cells. 2020 Apr 04;9(4):
pubmed: 32260326
Nat Methods. 2012 Jul 01;9(8):805-7
pubmed: 22751204
Science. 2020 May 29;368(6494):980-987
pubmed: 32467387
PLoS One. 2012;7(2):e32172
pubmed: 22384171
Genes (Basel). 2017 May 25;8(6):
pubmed: 28587062
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):20982-7
pubmed: 22158985
Cell. 2012 Sep 28;151(1):56-67
pubmed: 23021215
J Am Chem Soc. 2016 Jun 15;138(23):7429-35
pubmed: 27268299
Cell Chem Biol. 2019 May 16;26(5):711-723.e14
pubmed: 30880155
Mol Cell Biol. 2019 Oct 28;39(22):
pubmed: 31501275
Science. 1991 Mar 8;251(4998):1211-7
pubmed: 2006410
Angew Chem Int Ed Engl. 2010 Nov 22;49(48):9126-31
pubmed: 20815002
ACS Chem Biol. 2014 Aug 15;9(8):1662-7
pubmed: 24936957
Signal Transduct Target Ther. 2018 Feb 23;3:5
pubmed: 29527331
Nat Rev Cancer. 2008 Dec;8(12):976-90
pubmed: 19029958
Angew Chem Int Ed Engl. 2006 Feb 13;45(8):1248-52
pubmed: 16416482
J Am Chem Soc. 2021 Apr 14;143(14):5336-5342
pubmed: 33797881
Biochemistry. 2019 Sep 24;58(38):3980-3989
pubmed: 31450889
Biochim Biophys Acta. 2010 Jun;1798(6):1119-28
pubmed: 20214875
Mol Cancer. 2021 Jan 4;20(1):3
pubmed: 33397405
Nat Chem Biol. 2017 May;13(5):464-466
pubmed: 28244989
Nat Chem. 2017 Aug;9(8):762-771
pubmed: 28754949
Theranostics. 2019 Apr 25;9(10):2882-2896
pubmed: 31244930
Nat Chem Biol. 2019 Mar;15(3):276-284
pubmed: 30770915
Science. 1990 Nov 23;250(4984):1149-51
pubmed: 2251503
Oncogene. 2019 Jan;38(1):140-150
pubmed: 30076412
Oncogene. 1998 Nov 12;17(19):2463-72
pubmed: 9824157
Nat Commun. 2018 Aug 8;9(1):3154
pubmed: 30089783
Cancer Cell. 2019 Nov 11;36(5):483-497.e15
pubmed: 31679823
J Control Release. 2018 Jan 10;269:24-35
pubmed: 29113792
Cell. 2003 Jan 24;112(2):193-205
pubmed: 12553908
Cell. 2013 Mar 14;152(6):1237-51
pubmed: 23498934
Chem Sci. 2020 Aug 4;11(47):12633-12646
pubmed: 34123237
Anticancer Res. 2010 Oct;30(10):4193-200
pubmed: 21036740
Nature. 2018 Sep;561(7722):268-272
pubmed: 30158700
Acc Chem Res. 2014 Aug 19;47(8):2309-18
pubmed: 24877793
Cancer Res. 2007 Aug 15;67(16):7713-22
pubmed: 17699775
Curr Opin Chem Biol. 2010 Jun;14(3):331-40
pubmed: 20395165
Chem Rev. 2019 Jun 26;119(12):7328-7443
pubmed: 31050890
Biochim Biophys Acta Mol Cell Res. 2019 Mar;1866(3):430-440
pubmed: 30296497
Biochim Biophys Acta. 2015 May;1849(5):525-43
pubmed: 24657798
Chem Soc Rev. 2018 Dec 21;47(24):9046-9068
pubmed: 30418441
J Am Chem Soc. 2020 May 20;142(20):9124-9129
pubmed: 32364380
Science. 1994 Nov 4;266(5186):776-9
pubmed: 7973629
Chembiochem. 2012 Jan 23;13(2):293-7
pubmed: 22213387
Nature. 1993 May 6;363(6424):38-45
pubmed: 8479534
ACS Cent Sci. 2020 Sep 23;6(9):1564-1571
pubmed: 32999931
Nat Chem Biol. 2014 Aug;10(8):613-22
pubmed: 24929527
Oncogene. 2017 Apr 6;36(14):1911-1924
pubmed: 27748763
Nat Chem. 2016 Apr 22;8(5):407-18
pubmed: 27102674
Angew Chem Int Ed Engl. 2009;48(43):8090-4
pubmed: 19780082
Cell. 2018 Feb 8;172(4):650-665
pubmed: 29425488
ACS Cent Sci. 2021 Apr 28;7(4):641-649
pubmed: 34056094
Science. 2021 Jan 1;371(6524):57-64
pubmed: 33384371
Sci Transl Med. 2019 Mar 20;11(484):
pubmed: 30894502