Discovery of Potent 2-Aryl-6,7-dihydro-5$H$-pyrrolo[1,2-$a$]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

Wang, Feng; Jeon, Kyu Ok; Salovich, James M.; Macdonald, Jonathan D.; Alvarado, Joseph; Gogliotti, Rocco D.; Phan, Jason; Olejniczak, Edward T.; Sun, Qi; Wang, Shidong; Camper, DeMarco; Yuh, Joannes P.; Shaw, J. Grace; Sai, Jiqing; Rossanese, Olivia W.; Tansey, William P.; Stauffer, Shaun R.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.8b00375

Title: Discovery of Potent 2-Aryl-6,7-dihydro-5$$H$$-pyrrolo[1,2-$$a$$]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

Journal Article · Mon Jun 11 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00375· OSTI ID:1499757

Wang, Feng ^[1]; Jeon, Kyu Ok ^[1]; Salovich, James M. ^[1];

^[1]; Alvarado, Joseph ^[1]; Gogliotti, Rocco D. ^[1]; Phan, Jason ^[1]; Olejniczak, Edward T. ^[1]; Sun, Qi ^[1]; Wang, Shidong ^[1]; Camper, DeMarco ^[1]; Yuh, Joannes P. ^[1]; Shaw, J. Grace ^[1]; Sai, Jiqing ^[1]; Rossanese, Olivia W. ^[1]; Tansey, William P. ^[1]; Stauffer, Shaun R. ^[1];

^[1]

Vanderbilt Univ., Nashville, TN (United States)

WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. In this a paper, we describe the discovery of potent and selective WDR5-WINsite 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC); Michigan Economic Development Corporation and Michigan Technology Tri-Corridor; National Cancer Institute (NCI)

Grant/Contract Number:: 1S-10RR025677-01; AC02-06CH11357; 085P1000817; HHSN261200800001E; CA200709; CA68485

OSTI ID:: 1499757

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 13; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 31 works

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References (35)

The WD repeat: a common architecture for diverse functions Smith, Temple F.; Gaitatzes, Chrysanthe; Saxena, Kumkum Trends in Biochemical Sciences, Vol. 24, Issue 5 https://doi.org/10.1016/S0968-0004(99)01384-5	journal	May 1999
WD40 proteins propel cellular networks Stirnimann, Christian U.; Petsalaki, Evangelia; Russell, Robert B. Trends in Biochemical Sciences, Vol. 35, Issue 10 https://doi.org/10.1016/j.tibs.2010.04.003	journal	October 2010
Structure and function of WD40 domain proteins Xu, Chao; Min, Jinrong Protein & Cell, Vol. 2, Issue 3 https://doi.org/10.1007/s13238-011-1018-1	journal	March 2011
Moonlighting with WDR5: A Cellular Multitasker Guarnaccia, Alissa; Tansey, William Journal of Clinical Medicine, Vol. 7, Issue 2 https://doi.org/10.3390/jcm7020021	journal	January 2018
The Multifunctions of WD40 Proteins in Genome Integrity and Cell Cycle Progression Zhang, Caiguo; Zhang, Fan Journal of Genomics, Vol. 3 https://doi.org/10.7150/jgen.11015	journal	January 2015
Analysis of the Binding of Mixed Lineage Leukemia 1 (MLL1) and Histone 3 Peptides to WD Repeat Domain 5 (WDR5) for the Design of Inhibitors of the MLL1−WDR5 Interaction Karatas, Hacer; Townsend, Elizabeth C.; Bernard, Denzil Journal of Medicinal Chemistry, Vol. 53, Issue 14 https://doi.org/10.1021/jm100139b	journal	July 2010
WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma Sun, Yuting; Bell, Jessica L.; Carter, Daniel Cancer Research, Vol. 75, Issue 23 https://doi.org/10.1158/0008-5472.CAN-15-0423	journal	October 2015
WDR5 Expression Is Prognostic of Breast Cancer Outcome Dai, Xiaofeng; Guo, Wenwen; Zhan, Chunjun PLOS ONE, Vol. 10, Issue 9 https://doi.org/10.1371/journal.pone.0124964	journal	September 2015
Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation Chen, Xu; Xie, Weibin; Gu, Peng Scientific Reports, Vol. 5, Issue 1 https://doi.org/10.1038/srep08293	journal	February 2015
In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer Carugo, Alessandro; Genovese, Giannicola; Seth, Sahil Cell Reports, Vol. 16, Issue 1 https://doi.org/10.1016/j.celrep.2016.05.063	journal	June 2016
PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407 Tan, Xin; Chen, Shuai; Wu, Jiangxue Cell Death & Disease, Vol. 8, Issue 3 https://doi.org/10.1038/cddis.2017.111	journal	March 2017
Structure of WDR5 Bound to Mixed Lineage Leukemia Protein-1 Peptide Patel, Anamika; Dharmarajan, Venkatasubramanian; Cosgrove, Michael S. Journal of Biological Chemistry, Vol. 283, Issue 47 https://doi.org/10.1074/jbc.C800164200	journal	October 2008
WDR5 Interacts with Mixed Lineage Leukemia (MLL) Protein via the Histone H3-binding Pocket Song, Ji-Joon; Kingston, Robert E. Journal of Biological Chemistry, Vol. 283, Issue 50 https://doi.org/10.1074/jbc.M806900200	journal	October 2008
MLL: a histone methyltransferase disrupted in leukemia Hess, Jay L. Trends in Molecular Medicine, Vol. 10, Issue 10 https://doi.org/10.1016/j.molmed.2004.08.005	journal	October 2004
The MLL recombinome of acute leukemias in 2013 Meyer, C.; Hofmann, J.; Burmeister, T. Leukemia, Vol. 27, Issue 11 https://doi.org/10.1038/leu.2013.135	journal	April 2013
The Pathogenesis of Mixed-Lineage Leukemia Muntean, Andrew G.; Hess, Jay L. Annual Review of Pathology: Mechanisms of Disease, Vol. 7, Issue 1 https://doi.org/10.1146/annurev-pathol-011811-132434	journal	February 2012
MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches Winters, Amanda C.; Bernt, Kathrin M. Frontiers in Pediatrics, Vol. 5 https://doi.org/10.3389/fped.2017.00004	journal	February 2017
MLL-AF9-Induced Leukemogenesis Requires Coexpression of the Wild-Type Mll Allele Thiel, Austin T.; Blessington, Peter; Zou, Tao Cancer Cell, Vol. 17, Issue 2 https://doi.org/10.1016/j.ccr.2009.12.034	journal	February 2010
Multiple Interactions Recruit MLL1 and MLL1 Fusion Proteins to the HOXA9 Locus in Leukemogenesis Milne, Thomas A.; Kim, Jaehoon; Wang, Gang G. Molecular Cell, Vol. 38, Issue 6 https://doi.org/10.1016/j.molcel.2010.05.011	journal	June 2010
MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia Chen, Yufei; Anastassiadis, Konstantinos; Kranz, Andrea Cancer Cell, Vol. 31, Issue 6 https://doi.org/10.1016/j.ccell.2017.05.002	journal	June 2017
Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex Dias, J.; Van Nguyen, N.; Georgiev, P. Genes & Development, Vol. 28, Issue 9 https://doi.org/10.1101/gad.240200.114	journal	May 2014
Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC Thomas, Lance R.; Wang, Qingguo; Grieb, Brian C. Molecular Cell, Vol. 58, Issue 3 https://doi.org/10.1016/j.molcel.2015.02.028	journal	May 2015
High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein–Protein Interaction Karatas, Hacer; Townsend, Elizabeth C.; Cao, Fang Journal of the American Chemical Society, Vol. 135, Issue 2 https://doi.org/10.1021/ja306028q	journal	December 2012
Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia Cao, Fang; Townsend, Elizabeth C.; Karatas, Hacer Molecular Cell, Vol. 53, Issue 2 https://doi.org/10.1016/j.molcel.2013.12.001	journal	January 2014
Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction Karatas, Hacer; Li, Yangbing; Liu, Liu Journal of Medicinal Chemistry, Vol. 60, Issue 12 https://doi.org/10.1021/acs.jmedchem.6b01796	journal	June 2017
Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia Grebien, Florian; Vedadi, Masoud; Getlik, Matthäus Nature Chemical Biology, Vol. 11, Issue 8 https://doi.org/10.1038/nchembio.1859	journal	July 2015
Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1) Getlik, Matthäus; Smil, David; Zepeda-Velázquez, Carlos Journal of Medicinal Chemistry, Vol. 59, Issue 6 https://doi.org/10.1021/acs.jmedchem.5b01630	journal	March 2016
High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity Li, Dong-Dong; Chen, Wei-Lin; Wang, Zhi-Hui European Journal of Medicinal Chemistry, Vol. 124 https://doi.org/10.1016/j.ejmech.2016.08.036	journal	November 2016
Development and Use of Assay Conditions Suited to Screening for and Profiling of SET-Domain-Targeted Inhibitors of the MLL/SET1 Family of Lysine Methyltransferases Ferry, Joseph J.; Smith, Robert F.; Denney, Natalie ASSAY and Drug Development Technologies, Vol. 13, Issue 4 https://doi.org/10.1089/adt.2015.646	journal	May 2015
One-pot asymmetric synthesis of tert-butanesulfinyl-protected amines from ketones by the in situ reduction of tert-butanesulfinyl ketimines Borg, George; Cogan, Derek A.; Ellman, Jonathan A. Tetrahedron Letters, Vol. 40, Issue 37 https://doi.org/10.1016/S0040-4039(99)01351-9	journal	September 1999
Reversal of Diastereofacial Selectivity in Hydride Reductions of N - tert -Butanesulfinyl Imines Colyer, John T.; Andersen, Neil G.; Tedrow, Jason S. The Journal of Organic Chemistry, Vol. 71, Issue 18 https://doi.org/10.1021/jo0609834	journal	September 2006
SOFAST-HMQC Experiments for Recording Two-dimensional Deteronuclear Correlation Spectra of Proteins within a Few Seconds Schanda, Paul; Kupče, Ēriks; Brutscher, Bernhard Journal of Biomolecular NMR, Vol. 33, Issue 4 https://doi.org/10.1007/s10858-005-4425-x	journal	December 2005
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
A novel two-site binding equation presented in terms of the total ligand concentration Wang, Zhi-Xin; Jiang, Ruo-Fan FEBS Letters, Vol. 392, Issue 3 https://doi.org/10.1016/0014-5793(96)00818-6	journal	September 1996

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Targeting WDR5: A WINning Anti-Cancer Strategy? Aho, Erin R.; Weissmiller, April M.; Fesik, Stephen W. Epigenetics Insights, Vol. 12 https://doi.org/10.1177/2516865719865282	journal	January 2019
Direct defluorinative amidation–hydrolysis reaction of gem -difluoroalkenes with N , N -dimethylformamide, and primary and secondary amines Wang, Biyun; Zhao, Xianghu; Liu, Qingyun Organic & Biomolecular Chemistry, Vol. 16, Issue 44 https://doi.org/10.1039/c8ob02322k	journal	January 2018
Fragment screening for a protein-protein interaction inhibitor to WDR5 Dennis, Matthew L.; Morrow, Benjamin J.; Dolezal, Olan Structural Dynamics, Vol. 6, Issue 6 https://doi.org/10.1063/1.5122849	journal	November 2019
Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance Thomas, Lance R.; Adams, Clare M.; Wang, Jing Proceedings of the National Academy of Sciences, Vol. 116, Issue 50 https://doi.org/10.1073/pnas.1910391116	journal	November 2019
Expression of WD Repeat Domain 5 (WDR5) is Associated with Progression and Reduced Prognosis in Papillary Thyroid Carcinoma Xu, Wenchao; Wang, Lingling; An, Ying Medical Science Monitor, Vol. 25 https://doi.org/10.12659/msm.915847	journal	May 2019

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Title: Discovery of Potent 2-Aryl-6,7-dihydro-5$$H$$-pyrrolo[1,2-$$a$$]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

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