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BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.5 billion molecules from our DNA-encoded chemical libraries with BRDT-BD1 or BRDT-BD2 proteins in parallel. A compound series enriched only by BRDT-BD1 was resynthesized off-DNA, uncovering a potent chiral compound, CDD-724, with >2,000-fold selectivity for inhibiting BRDT-BD1 over BRDT-BD2. CDD-724 stereoisomers exhibited remarkable differences in inhibiting BRDT-BD1, with the R-enantiomer (CDD-787) being 50-fold more potent than the S-enantiomer (CDD-786). From structure–activity relationship studies, we produced CDD-956, which maintained picomolar BET BD1 binding potency and high selectivity over BET BD2 proteins and had improved stability in human liver microsomes over CDD-787. BROMOscan profiling confirmed the excellent pan-BET BD1 affinity and selectivity of CDD-787 and CDD-956 on BD1 versus BD2 and all other BD-containing proteins. A cocrystal structure of BRDT-BD1 bound with CDD-956 was determined at 1.82 Å and revealed BRDT-BD1–specific contacts with the αZ and αC helices that explain the high affinity and selectivity for BET BD1 versus BD2. CDD-787 and CDD-956 maintain cellular BD1-selectivity in NanoBRET assays and show potent antileukemic activity in acute myeloid leukemia cell lines. These BET BD1-specific and highly potent compounds are structurally unique and provide insight into the importance of chirality to achieve BET specificity.

Titel:	Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.
Autor/in / Beteiligte Person:	Modukuri, RK ; Yu, Z ; Tan, Z ; Ta, HM ; Ucisik, MN ; Jin, Z ; Anglin, JL ; Sharma, KL ; Nyshadham, P ; Li, F ; Riehle, K ; Faver, JC ; Duong, K ; Nagarajan, S ; Simmons, N ; Palmer, SS ; Teng, M ; Young, DW ; Yi, JS ; Kim, C ; Matzuk, MM
Link:	Full Text Finder (Volltext)
Zeitschrift:	Proceedings of the National Academy of Sciences of the United States of America, Jg. 119 (2022-05-31), Heft 22, S. e2122506119
Veröffentlichung:	Washington, DC : National Academy of Sciences, 2022
Medientyp:	academicJournal
ISSN:	1091-6490 (electronic)
DOI:	10.1073/pnas.2122506119
Schlagwort:	DNA genetics Humans Male Protein Domains Structure-Activity Relationship Anti-Inflammatory Agents, Non-Steroidal chemistry Anti-Inflammatory Agents, Non-Steroidal isolation & purification Anti-Inflammatory Agents, Non-Steroidal pharmacology Antineoplastic Agents chemistry Antineoplastic Agents isolation & purification Antineoplastic Agents pharmacology Contraceptive Agents, Male chemistry Contraceptive Agents, Male isolation & purification Contraceptive Agents, Male pharmacology Drug Discovery Nuclear Proteins antagonists & inhibitors Nuclear Proteins chemistry Small Molecule Libraries chemistry Small Molecule Libraries isolation & purification Small Molecule Libraries pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Proc Natl Acad Sci U S A] 2022 May 31; Vol. 119 (22), pp. e2122506119. <i>Date of Electronic Publication: </i>2022 May 27. MeSH Terms: Anti-Inflammatory Agents, Non-Steroidal* / chemistry ; Anti-Inflammatory Agents, Non-Steroidal* / isolation & purification ; Anti-Inflammatory Agents, Non-Steroidal* / pharmacology ; Antineoplastic Agents* / chemistry ; Antineoplastic Agents* / isolation & purification ; Antineoplastic Agents* / pharmacology ; Contraceptive Agents, Male* / chemistry ; Contraceptive Agents, Male* / isolation & purification ; Contraceptive Agents, Male* / pharmacology ; Drug Discovery* ; Nuclear Proteins* / antagonists & inhibitors ; Nuclear Proteins* / chemistry ; Small Molecule Libraries* / chemistry ; Small Molecule Libraries* / isolation & purification ; Small Molecule Libraries* / pharmacology ; DNA / genetics ; Humans ; Male ; Protein Domains ; Structure-Activity Relationship References: J Med Chem. 2019 Dec 26;62(24):11080-11107. (PMID: 31789032) ; J Med Chem. 2016 Feb 25;59(4):1518-30. (PMID: 26731611) ; J Med Chem. 2018 Oct 25;61(20):9316-9334. (PMID: 30253095) ; Pharmacol Ther. 2020 Apr;208:107479. (PMID: 31931101) ; J Med Chem. 2020 Sep 10;63(17):9020-9044. (PMID: 32787145) ; Nature. 2020 Feb;578(7794):306-310. (PMID: 31969702) ; ACS Comb Sci. 2019 Feb 11;21(2):75-82. (PMID: 30672692) ; Angew Chem Int Ed Engl. 2020 Aug 24;59(35):14965-14972. (PMID: 32436364) ; J Med Chem. 2017 Jun 8;60(11):4533-4558. (PMID: 28195723) ; Cell. 2017 Jul 27;170(3):564-576.e16. (PMID: 28753430) ; PLoS One. 2013 Dec 31;8(12):e83190. (PMID: 24391744) ; Dev Biol. 2011 Dec 15;360(2):358-68. (PMID: 22020252) ; Bioorg Med Chem. 2021 Sep 1;45:116328. (PMID: 34364223) ; Mar Drugs. 2018 Jun 12;16(6):. (PMID: 29895761) ; J Med Chem. 2013 Nov 27;56(22):9251-64. (PMID: 24144283) ; Science. 2020 Apr 24;368(6489):387-394. (PMID: 32193360) ; Nat Commun. 2016 Dec 19;7:13855. (PMID: 27991587) ; Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):. (PMID: 33637650) ; Biol Reprod. 2020 Aug 4;103(2):427-436. (PMID: 32285106) ; Nature. 2010 Dec 23;468(7327):1067-73. (PMID: 20871596) ; Nat Rev Mol Cell Biol. 2017 Apr;18(4):246-262. (PMID: 28053347) ; Nat Commun. 2017 Nov 22;8(1):1707. (PMID: 29167426) ; Cell. 2012 Aug 17;150(4):673-84. (PMID: 22901802) ; Nucleic Acids Res. 1994 Dec 11;22(24):5332-40. (PMID: 7816623) ; Chem Biol. 2014 Jul 17;21(7):841-854. (PMID: 24954007) ; J Med Chem. 2016 Feb 25;59(4):1634-41. (PMID: 26735842) ; Cancer Res. 2020 Sep 1;80(17):3507-3518. (PMID: 32651255) ; J Med Chem. 2020 Sep 10;63(17):9045-9069. (PMID: 32691589) ; Chem Biol Drug Des. 2021 May;97(5):1117-1128. (PMID: 33638254) ; Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):2952-2957. (PMID: 28265070) ; Viruses. 2013 Jun 21;5(6):1571-86. (PMID: 23793227) ; Cell. 2021 Apr 15;184(8):2167-2182.e22. (PMID: 33811809) ; Front Pharmacol. 2021 Jan 26;11:621093. (PMID: 33574760) ; Development. 2007 Oct;134(19):3507-15. (PMID: 17728347) ; Cold Spring Harb Perspect Biol. 2014 Jun 02;6(6):. (PMID: 24890512) Grant Information: P01HD087157 HHS \| NIH \| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); 5K12CA090433-17 HHS \| NIH \| National Cancer Institute (NCI); R01DK121970 HHS \| NIH \| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); R61HD099995 HHS \| NIH \| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); S10 RR028976 United States RR NCRR NIH HHS; S10 OD027000 United States OD NIH HHS Contributed Indexing: Keywords: BET bromodomains; BRDT; DNA-encoded chemistry technology; small-molecule inhibitors Substance Nomenclature: 0 (Anti-Inflammatory Agents, Non-Steroidal) ; 0 (Antineoplastic Agents) ; 0 (BRDT protein, human) ; 0 (Contraceptive Agents, Male) ; 0 (Nuclear Proteins) ; 0 (Small Molecule Libraries) ; 9007-49-2 (DNA) Entry Date(s): Date Created: 20220527 Date Completed: 20220531 Latest Revision: 20220721 Update Code: 20231215 PubMed Central ID: PMC9295786

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Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.