دورية أكاديمية
أعرض في EDS

Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.

التفاصيل البيبلوغرافية
العنوان: Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.
المؤلفون: Garnar-Wortzel L; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Bishop TR; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Kitamura S; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States.; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United States., Milosevich N; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Asiaban JN; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Zhang X; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Zheng Q; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Chen E; California Institute for Biomedical Research, The Scripps Research Institute, La Jolla, California 92037, United States., Ramos AR; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Ackerman CJ; California Institute for Biomedical Research, The Scripps Research Institute, La Jolla, California 92037, United States., Hampton EN; California Institute for Biomedical Research, The Scripps Research Institute, La Jolla, California 92037, United States., Chatterjee AK; California Institute for Biomedical Research, The Scripps Research Institute, La Jolla, California 92037, United States., Young TS; California Institute for Biomedical Research, The Scripps Research Institute, La Jolla, California 92037, United States., Hull MV; California Institute for Biomedical Research, The Scripps Research Institute, La Jolla, California 92037, United States., Sharpless KB; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Cravatt BF; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States., Wolan DW; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States.; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United States., Erb MA; Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
المصدر: ACS central science [ACS Cent Sci] 2021 May 26; Vol. 7 (5), pp. 815-830. Date of Electronic Publication: 2021 Apr 30.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: ACS Publications Country of Publication: United States NLM ID: 101660035 Publication Model: Print-Electronic Cited Medium: Print ISSN: 2374-7943 (Print) Linking ISSN: 23747943 NLM ISO Abbreviation: ACS Cent Sci Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Washington DC : ACS Publications, [2015]-
مستخلص: Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC 50 = 7 μM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC 50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10 , MYB , MYC , and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain.
Competing Interests: The authors declare the following competing financial interest(s): S.K., A.K.C., D.W.W., and M.A.E are inventors on patent applications related to the molecules disclosed in this manuscript.
(© 2021 The Authors. Published by American Chemical Society.)
References: Nature. 2017 Mar 9;543(7644):265-269. (PMID: 28241141)
EMBO J. 1998 Jul 1;17(13):3714-25. (PMID: 9649441)
Cancer Cell. 2011 Jul 12;20(1):53-65. (PMID: 21741596)
Cancer Res. 2015 Sep 15;75(18):3865-3878. (PMID: 26139243)
Cell Chem Biol. 2017 Sep 21;24(9):1181-1190. (PMID: 28648379)
Genes Dev. 2013 Dec 15;27(24):2648-62. (PMID: 24285714)
Cancer Res. 2013 Sep 1;73(17):5508-18. (PMID: 23872584)
Nat Genet. 2021 Mar;53(3):269-278. (PMID: 33558760)
Blood. 2017 Jan 26;129(4):497-508. (PMID: 27756750)
J Biomol Screen. 1999;4(2):67-73. (PMID: 10838414)
Leukemia. 2002 Feb;16(2):186-95. (PMID: 11840284)
Cell. 2020 Aug 20;182(4):1009-1026.e29. (PMID: 32730809)
Nat Rev Cancer. 2007 Nov;7(11):823-33. (PMID: 17957188)
Blood. 2018 Feb 8;131(6):662-673. (PMID: 29217648)
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3128-33. (PMID: 24520176)
Leukemia. 1999 Dec;13(12):1993-9. (PMID: 10602420)
Mol Cell. 2017 Jul 6;67(1):5-18.e19. (PMID: 28673542)
N Engl J Med. 2004 Apr 15;350(16):1617-28. (PMID: 15084694)
Mol Cell Biol. 2014 Mar;34(6):1136-44. (PMID: 24421395)
ACS Med Chem Lett. 2019 Nov 25;10(12):1661-1666. (PMID: 31857843)
Science. 2014 Jan 17;343(6168):301-5. (PMID: 24292625)
Oncogene. 2007 Oct 15;26(47):6766-76. (PMID: 17934484)
Leuk Res. 2000 Oct;24(10):849-55. (PMID: 10996203)
SLAS Discov. 2019 Feb;24(2):133-141. (PMID: 30359161)
N Engl J Med. 2013 May 30;368(22):2059-74. (PMID: 23634996)
Nat Rev Cancer. 2017 Jul;17(7):425-440. (PMID: 28524181)
Nature. 2011 Aug 03;478(7370):524-8. (PMID: 21814200)
J Med Chem. 2018 Dec 13;61(23):10929-10934. (PMID: 30407816)
Nat Chem Biol. 2018 Apr;14(4):405-412. (PMID: 29507391)
Nat Chem Biol. 2018 May;14(5):431-441. (PMID: 29581585)
Cell Rep. 2018 Aug 14;24(7):1722-1729. (PMID: 30110629)
Cell. 2010 Oct 15;143(2):313-24. (PMID: 20946988)
Angew Chem Int Ed Engl. 2019 Jun 11;58(24):8029-8033. (PMID: 30998840)
Nat Chem Biol. 2019 Jul;15(7):672-680. (PMID: 31178587)
Nat Genet. 2002 Jan;30(1):41-7. (PMID: 11731795)
Cell Chem Biol. 2019 Feb 21;26(2):300-306.e9. (PMID: 30595531)
Science. 1999 Oct 15;286(5439):531-7. (PMID: 10521349)
Blood. 2005 Aug 1;106(3):899-902. (PMID: 15831697)
Genes Dev. 2011 Aug 1;25(15):1628-40. (PMID: 21828272)
Angew Chem Int Ed Engl. 2018 Dec 10;57(50):16302-16307. (PMID: 30288907)
Nat Chem Biol. 2018 Dec;14(12):1140-1149. (PMID: 30374167)
Science. 2014 Jan 17;343(6168):305-9. (PMID: 24292623)
Mol Cell. 2016 Apr 21;62(2):181-193. (PMID: 27105114)
Biochem Cell Biol. 2009 Feb;87(1):65-75. (PMID: 19234524)
Cell. 2012 Mar 30;149(1):214-31. (PMID: 22464331)
Nat Genet. 2021 Mar;53(3):279-287. (PMID: 33558757)
J Med Chem. 2018 Nov 21;61(22):10155-10172. (PMID: 30339381)
ACS Chem Biol. 2020 Apr 17;15(4):895-903. (PMID: 32176478)
J Am Chem Soc. 2020 Jun 24;142(25):10899-10904. (PMID: 32479075)
Nature. 2017 Mar 9;543(7644):270-274. (PMID: 28241139)
Science. 2018 May 18;360(6390):800-805. (PMID: 29622725)
معلومات مُعتمدة: DP5 OD026380 United States OD NIH HHS; K99 GM138758 United States GM NIGMS NIH HHS
تواريخ الأحداث: Date Created: 20210603 Latest Revision: 20210707
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8161486
DOI: 10.1021/acscentsci.0c01550
PMID: 34079898
قاعدة البيانات: MEDLINE
الوصف
تدمد:2374-7943
DOI:10.1021/acscentsci.0c01550