Structure-based discovery of potent WD repeat domain 5&nbsp;inhibitors that demonstrate efficacy and safety in preclinical animal models

Teuscher, Kevin B.; Chowdhury, Somenath; Meyers, Kenneth M.; Tian, Jianhua; Sai, Jiqing; Van Meveren, Mayme; South, Taylor M.; Sensintaffar, John L.; Rietz, Tyson A.; Goswami, Soumita; Wang, Jing; Grieb, Brian C.; Lorey, Shelly L.; Howard, Gregory C.; Liu, Qi; Moore, William J.; Stott, Gordon M.; Tansey, William P.; Lee, Taekyu; Fesik, Stephen W.

doi:10.1073/pnas.2211297120

Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models

Journal Article · Mon Dec 26 23:00:00 EST 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2211297120· OSTI ID:2470237

Teuscher, Kevin B. ^[1]; Chowdhury, Somenath ^[1]; ^[1]; ^[2]; Sai, Jiqing ^[1]; Van Meveren, Mayme ^[1]; South, Taylor M. ^[1]; Sensintaffar, John L. ^[1]; Rietz, Tyson A. ^[1]; ^[1]; Wang, Jing ^[3]; ^[4]; Lorey, Shelly L. ^[1]; ^[1]; ^[3]; ^[5]; ^[6]; ^[1]; Lee, Taekyu ^[1]; ^[7]

Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Vanderbilt Univ., Nashville, TN (United States)
Vanderbilt Univ. Medical Center, Nashville, TN (United States)
Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ. Medical Center, Nashville, TN (United States)
National Cancer Institute, Frederick, MD (United States)
Frederick National Laboratory for Cancer Research, Frederick, MD (United States)
Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)

WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P₇ units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.

View Accepted Manuscript (DOE)

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

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470237

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 1 Vol. 120; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

References (53)

Up‐regulated WDR5 promotes gastric cancer formation by induced cyclin D1 expression Sun, Wei; Guo, Fuchao; Liu, Mingkai Journal of Cellular Biochemistry, Vol. 119, Issue 4 https://doi.org/10.1002/jcb.26491	journal	December 2017
Human Genome and Diseases:¶WD-repeat proteins: structure characteristics, biological function, and their involvement in human diseases Li, D.; Roberts, R. Cellular and Molecular Life Sciences, Vol. 58, Issue 14 https://doi.org/10.1007/PL00000838	journal	December 2001
WD40 Repeat Proteins: Signalling Scaffold with Diverse Functions Jain, Buddhi Prakash; Pandey, Shweta The Protein Journal, Vol. 37, Issue 5 https://doi.org/10.1007/s10930-018-9785-7	journal	August 2018
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
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
Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis Zhang, Xiong; Zheng, Xingling; Yang, Hong Cancer Letters, Vol. 431 https://doi.org/10.1016/j.canlet.2018.05.034	journal	September 2018
Defining a Cancer Dependency Map Tsherniak, Aviad; Vazquez, Francisca; Montgomery, Phil G. Cell, Vol. 170, Issue 3 https://doi.org/10.1016/j.cell.2017.06.010	journal	July 2017
Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening McDonald, E. Robert; de Weck, Antoine; Schlabach, Michael R. Cell, Vol. 170, Issue 3 https://doi.org/10.1016/j.cell.2017.07.005	journal	July 2017
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
Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity Aho, Erin R.; Wang, Jing; Gogliotti, Rocco D. Cell Reports, Vol. 26, Issue 11 https://doi.org/10.1016/j.celrep.2019.02.047	journal	March 2019
Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5 Li, Dong-Dong; Chen, Wei-Lin; Xu, Xiao-Li European Journal of Medicinal Chemistry, Vol. 118 https://doi.org/10.1016/j.ejmech.2016.04.032	journal	August 2016
A Twist1-MLL-WDR5-HOTTIP Complex Regulates HOXA9 Chromatin to Facilitate Metastasis of Prostate Cancer Tran, P. T.; Gajula, R.; Williams, R. International Journal of Radiation OncologyBiologyPhysics, Vol. 90, Issue 1 https://doi.org/10.1016/j.ijrobp.2014.05.691	journal	September 2014
Structural Basis for the Specific Recognition of Methylated Histone H3 Lysine 4 by the WD-40 Protein WDR5 Han, Zhifu; Guo, Lan; Wang, Huayi Molecular Cell, Vol. 22, Issue 1 https://doi.org/10.1016/j.molcel.2006.03.018	journal	April 2006
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
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
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
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
Targeting WD Repeat-Containing Protein 5 (WDR5): A Medicinal Chemistry Perspective Chen, Xin; Xu, Junjie; Wang, Xianghan Journal of Medicinal Chemistry, Vol. 64, Issue 15 https://doi.org/10.1021/acs.jmedchem.1c00037	journal	July 2021
Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization Teuscher, Kevin B.; Meyers, Kenneth M.; Wei, Qiangqiang Journal of Medicinal Chemistry, Vol. 65, Issue 8 https://doi.org/10.1021/acs.jmedchem.2c00195	journal	April 2022
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
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
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. Journal of Medicinal Chemistry, Vol. 61, Issue 13 https://doi.org/10.1021/acs.jmedchem.8b00375	journal	June 2018
Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core Tian, Jianhua; Teuscher, Kevin B.; Aho, Erin R. Journal of Medicinal Chemistry, Vol. 63, Issue 2 https://doi.org/10.1021/acs.jmedchem.9b01608	journal	December 2019
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
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
Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth Zhu, Jiajun; Sammons, Morgan A.; Donahue, Greg Nature, Vol. 525, Issue 7568 https://doi.org/10.1038/nature15251	journal	September 2015
Structural basis for activity regulation of MLL family methyltransferases Li, Yanjing; Han, Jianming; Zhang, Yuebin Nature, Vol. 530, Issue 7591 https://doi.org/10.1038/nature16952	journal	February 2016
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
Molecular recognition of histone H3 by the WD40 protein WDR5 Couture, Jean-François; Collazo, Evys; Trievel, Raymond C. Nature Structural & Molecular Biology, Vol. 13, Issue 8 https://doi.org/10.1038/nsmb1116	journal	July 2006
WIN site inhibition disrupts a subset of WDR5 function Siladi, Andrew J.; Wang, Jing; Florian, Andrea C. Scientific Reports, Vol. 12, Issue 1 https://doi.org/10.1038/s41598-022-05947-9	journal	February 2022
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
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
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
Characterization of a Novel WDR5-binding Site That Recruits RbBP5 through a Conserved Motif to Enhance Methylation of Histone H3 Lysine 4 by Mixed Lineage Leukemia Protein-1 Odho, Zain; Southall, Stacey M.; Wilson, Jon R. Journal of Biological Chemistry, Vol. 285, Issue 43 https://doi.org/10.1074/jbc.M110.159921	journal	August 2010
Structural Basis for WDR5 Interaction (Win) Motif Recognition in Human SET1 Family Histone Methyltransferases Dharmarajan, Venkatasubramanian; Lee, Jeong-Heon; Patel, Anamika Journal of Biological Chemistry, Vol. 287, Issue 33 https://doi.org/10.1074/jbc.M112.364125	journal	June 2012
Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes Alicea-Velázquez, Nilda L.; Shinsky, Stephen A.; Loh, Daniel M. Journal of Biological Chemistry, Vol. 291, Issue 43 https://doi.org/10.1074/jbc.M116.752626	journal	August 2016
A Conserved Arginine-containing Motif Crucial for the Assembly and Enzymatic Activity of the Mixed Lineage Leukemia Protein-1 Core Complex Patel, Anamika; Vought, Valarie E.; Dharmarajan, Venkatasubramanian Journal of Biological Chemistry, Vol. 283, Issue 47 https://doi.org/10.1074/jbc.M806317200	journal	October 2008
Targeting MYC through WDR5 Thomas, Lance R.; Adams, Clare M.; Fesik, Stephen W. Molecular & Cellular Oncology, Vol. 7, Issue 2 https://doi.org/10.1080/23723556.2019.1709388	journal	January 2020
WDR5 is a conserved regulator of protein synthesis gene expression Bryan, Audra F.; Wang, Jing; Howard, Gregory C. Nucleic Acids Research, Vol. 48, Issue 6 https://doi.org/10.1093/nar/gkaa051	journal	January 2020
Proteolysis‐targeting chimeras in drug development: A safety perspective Moreau, Kevin; Coen, Muireann; Zhang, Andrew X. British Journal of Pharmacology, Vol. 177, Issue 8 https://doi.org/10.1111/bph.15014	journal	February 2020
Overexpression of WD repeat domain 5 associates with aggressive clinicopathological features and unfavorable prognosis in head neck squamous cell carcinoma Wu, Yaping; Diao, Pengfei; Li, Zhongwu Journal of Oral Pathology & Medicine, Vol. 47, Issue 5 https://doi.org/10.1111/jop.12708	journal	April 2018
A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models Yu, Xufen; Li, Dongxu; Kottur, Jithesh Science Translational Medicine, Vol. 13, Issue 613 https://doi.org/10.1126/scitranslmed.abj1578	journal	September 2021
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
TWIST1-WDR5- Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis Malek, Reem; Gajula, Rajendra P.; Williams, Russell D. Cancer Research, Vol. 77, Issue 12 https://doi.org/10.1158/0008-5472.CAN-16-2797	journal	May 2017
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
Clinical Significance of WDR5 High Expression and Its Effect on Tumorigenesis in Adult Leukemia Ge, Zheng; Song, Evelyn; Li, Jianyong Blood, Vol. 126, Issue 23 https://doi.org/10.1182/blood.V126.23.3657.3657	journal	December 2015
WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage Neilsen, Beth K.; Chakraborty, Binita; McCall, Jamie L. BMC Cancer, Vol. 18, Issue 1 https://doi.org/10.1186/s12885-018-4580-6	journal	June 2018
WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells Punzi, Simona; Balestrieri, Chiara; D’Alesio, Carolina Breast Cancer Research, Vol. 21, Issue 1 https://doi.org/10.1186/s13058-019-1216-y	journal	November 2019
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
WDR5 high expression and its effect on tumorigenesis in leukemia Ge, Zheng; Song, Evelyn J.; Kawasawa, Yuka Imamura Oncotarget, Vol. 7, Issue 25 https://doi.org/10.18632/oncotarget.9312	journal	May 2016
The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer Lu, Kebin; Tao, He; Si, Xiaomin Frontiers in Oncology, Vol. 8 https://doi.org/10.3389/fonc.2018.00502	journal	November 2018
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
MLL1/WDR5 complex in leukemogenesis and epigenetic regulation Wu, Min; Shu, Hong-Bing Chinese Journal of Cancer, Vol. 30, Issue 4 https://doi.org/10.5732/cjc.011.10055	journal	April 2011

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