Discovery of Potent 2‑Aryl-6,7-dihydro‑5H‑pyrrolo[1,2‑a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design
WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based desig...
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| Published in | Journal of medicinal chemistry Vol. 61; no. 13; pp. 5623 - 5642 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
12.07.2018
Amer Chemical Soc |
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| Abstract | WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer. |
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| AbstractList | WDR5 is a chromatin regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed lineage leukemia. Here we describe the discovery of potent and selective WDR5 WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN-site within WDR5. Members of a 6,7-dihydro-5
H
-pyrrolo[1,2-
a
]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants < 10 nM and micromolar cellular activity against an AML leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer. WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer. WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5H-pyrrolo[l,2-a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer. |
| Author | Rossanese, Olivia W Yuh, Joannes P Wang, Shidong Shaw, J. Grace Olejniczak, Edward T Phan, Jason Jeon, Kyu Ok Stauffer, Shaun R Wang, Feng Salovich, James M Gogliotti, Rocco D Sun, Qi Sai, Jiqing Tansey, William P Fesik, Stephen W Camper, DeMarco Macdonald, Jonathan D Alvarado, Joseph |
| AuthorAffiliation | Department of Pharmacology Department of Chemistry Department of Cell and Developmental Biology Department of Biochemistry Vanderbilt University |
| AuthorAffiliation_xml | – name: Department of Cell and Developmental Biology – name: – name: Department of Pharmacology – name: Department of Chemistry – name: Vanderbilt University – name: Department of Biochemistry – name: Department of Cell and Developmental Biology Vanderbilt University, Nashville, Tennessee 37232 – name: Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 – name: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232 – name: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232 |
| Author_xml | – sequence: 1 givenname: Feng surname: Wang fullname: Wang, Feng – sequence: 2 givenname: Kyu Ok surname: Jeon fullname: Jeon, Kyu Ok – sequence: 3 givenname: James M surname: Salovich fullname: Salovich, James M – sequence: 4 givenname: Jonathan D orcidid: 0000-0002-6360-2768 surname: Macdonald fullname: Macdonald, Jonathan D – sequence: 5 givenname: Joseph surname: Alvarado fullname: Alvarado, Joseph – sequence: 6 givenname: Rocco D surname: Gogliotti fullname: Gogliotti, Rocco D – sequence: 7 givenname: Jason surname: Phan fullname: Phan, Jason – sequence: 8 givenname: Edward T surname: Olejniczak fullname: Olejniczak, Edward T – sequence: 9 givenname: Qi surname: Sun fullname: Sun, Qi – sequence: 10 givenname: Shidong surname: Wang fullname: Wang, Shidong – sequence: 11 givenname: DeMarco surname: Camper fullname: Camper, DeMarco – sequence: 12 givenname: Joannes P surname: Yuh fullname: Yuh, Joannes P – sequence: 13 givenname: J. Grace surname: Shaw fullname: Shaw, J. Grace – sequence: 14 givenname: Jiqing surname: Sai fullname: Sai, Jiqing – sequence: 15 givenname: Olivia W surname: Rossanese fullname: Rossanese, Olivia W – sequence: 16 givenname: William P surname: Tansey fullname: Tansey, William P – sequence: 17 givenname: Shaun R surname: Stauffer fullname: Stauffer, Shaun R – sequence: 18 givenname: Stephen W orcidid: 0000-0001-5957-6192 surname: Fesik fullname: Fesik, Stephen W email: Stephen.fesik@vanderbilt.edu |
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| Cites_doi | 10.1021/ja306028q 10.1038/leu.2013.135 10.1074/jbc.C800164200 10.1074/jbc.M806317200 10.1158/0008-5472.CAN-15-0423 10.1016/j.molmed.2004.08.005 10.1016/j.celrep.2016.05.063 10.1021/jo0609834 10.1107/S0907444902016657 10.1016/j.molcel.2015.02.028 10.1007/s10858-005-4425-x 10.1074/jbc.M806900200 10.1016/j.ejmech.2016.08.036 10.1016/j.ccr.2009.12.034 10.1101/gad.240200.114 10.3390/jcm7020021 10.1016/j.tibs.2010.04.003 10.1107/S0907444910045749 10.1038/cddis.2017.111 10.1016/j.molcel.2013.12.001 10.1016/j.ccell.2017.05.002 10.1007/s13238-011-1018-1 10.1021/acs.jmedchem.6b01796 10.1038/NCHEMBIO.1859 10.1371/journal.pone.0124964 10.3389/fped.2017.00004 10.1089/adt.2015.646 10.7150/jgen.11015 10.1021/acs.jmedchem.5b01630 10.1021/jm100139b 10.1146/annurev-pathol-011811-132434 10.1016/j.molcel.2010.05.011 |
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| Keywords | HIGH-AFFINITY COMPLEX LINEAGE BINDING WD REPEAT LEUKEMIA MLL PROTEIN |
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| Notes | Present Addresses: F.W.: Novartis Institutes for Biomedical Research, CA, USA; Q.S.: AbbVie, IL, USA; S.W.: Cell Signaling Technology, MA, USA; D.C.: Bristol-Meyers Squibb, MA, USA; O.W.R.: The Institute of Cancer Research, London, UK F.W. and K.O.J. contributed equally to this work. All authors have given approval to the final version of the manuscript. |
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| References | Winn, MD (WOS:000288532800002) 2011; 67 Zhang, Caiguo (MEDLINE:25653723) 2015; 3 Guarnaccia, AD (WOS:000427522200011) 2018; 7 Patel, A (WOS:000260893700002) 2008; 283 Milne, TA (WOS:000279297500010) 2010; 38 Sun, YT (WOS:000365603000014) 2015; 75 Otwinowski, Z (WOS:A1997BH42P00020) 1997; 276 Ferry, JJ (WOS:000363904600005) 2015; 13 Karatas, H (WOS:000313920800034) 2013; 135 Thiel, AT (WOS:000274766800007) 2010; 17 Muntean, AG (WOS:000301837300012) 2012; 7 Grebien, F (WOS:000358255300011) 2015; 11 Patel, A (WOS:000260893700003) 2008; 283 Thomas, LR (WOS:000354178800007) 2015; 58 Winters, AC (WOS:000393618600001) 2017; 5 Adams, PD (WOS:000178745000009) 2002; 58 Smith, TF (WOS:000080291300007) 1999; 24 Karatas, H (WOS:000279787200009) 2010; 53 Stirnimann, CU (WOS:000283411100005) 2010; 35 Getlik, M (WOS:000372946500015) 2016; 59 Li, DD (WOS:000388544600040) 2016; 124 Karatas, H (WOS:000404202200004) 2017; 60 Colyer, JT (WOS:000240020100020) 2006; 71 Schanda, P (WOS:000233868400001) 2005; 33 Dai, XF (WOS:000360965800001) 2015; 10 Carugo, A (WOS:000378950700013) 2016; 16 Dias, J (WOS:000335451400003) 2014; 28 Song, JJ (WOS:000261469100081) 2008; 283 Tan, X (WOS:000397447100049) 2017; 8 Xu, C (WOS:000310519700005) 2011; 2 Chen, YF (WOS:000403074800006) 2017; 31 Meyer, C (WOS:000326882500007) 2013; 27 Cao, F (WOS:000330496400008) 2014; 53 CHEN X (WOS:000439006100012.5) 2015; 5 Wang, ZX (WOS:A1996VF85500010) 1996; 392 Hess, JL (WOS:000224714700006) 2004; 10 Borg, G (WOS:000082199900003) 1999; 40 |
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| Snippet | WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage... WDR5 is a chromatin regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed lineage... |
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| SubjectTerms | Chemistry, Medicinal Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology |
| Title | Discovery of Potent 2‑Aryl-6,7-dihydro‑5H‑pyrrolo[1,2‑a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design |
| URI | http://dx.doi.org/10.1021/acs.jmedchem.8b00375 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000439006100012 https://pubmed.ncbi.nlm.nih.gov/PMC6842305 |
| Volume | 61 |
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