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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Strategic fluorination to achieve a potent, selective, metabolically stable, and orally bioavailable inhibitor of CSNK2 Han Wee Ong , Xuan Yang , Jeffery L. Smith , Sharon Taft-Benz , Stefanie Howell , Rebekah J. Dickmander , Tammy M. Havener , Marcia K. Sanders , Jason W. Brown , Rafael M. Counago , Edcon Chang , Andreas Kramer , Nathaniel J. Moorman , Mark Heise , Alison D. Axtman , David H. Drewry , Timothy M. Willson Molecules 29 DOI: 10.3390/molecules29174158 Diamond Proposal Number(s): [36057] Open Access Show Abstract ▼ Abstract: The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition.	Sep 2025
	Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open Claudia Tredup , Suzanne Ackloo , Hartmut Beck , Peter J. Brown , Alex N. Bullock , Alessio Ciulli , Ivan Dikic , Kristina Edfeldt , Aled M. Edwards , Jonathan M. Elkins , Henner F. Farin , Edward A. Fon , Matthias Gstaiger , Judith Günther , Anna-Lena Gustavsson , Sandra Häberle , Laura Isigkeit , Kilian V. M. Huber , Andras Kotschy , Oliver Krämer , Andrew R. Leach , Brian D. Marsden , Hisanori Matsui , Daniel Merk , Florian Montel , Monique P. C. Mulder , Susanne Müller , Dafydd R. Owen , Ewgenij Proschak , Sandra Röhm , Alexandra Stolz , Michael Sundström , Frank Von Delft , Timothy M. Willson , Cheryl H. Arrowsmith , Stefan Knapp Rsc Medicinal Chemistry 11 DOI: 10.1039/D4MD00735B Open Access Show Abstract ▼ Abstract: Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public–private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.	Nov 2024
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer’s disease Yuhong Du , William J. Bradshaw , Tina M. Leisner , Joel K. Annor-Gyamfi , Kun Qian , Frances M. Bashore , Arunima Sikdar , Felix O. Nwogbo , Andrey A. Ivanov , Stephen V. Frye , Opher Gileadi , Paul E. Brennan , Allan I. Levey , Alison D. Axtman , Kenneth H. Pearce , Haian Fu , Vittorio L. Katis , Ishita Ajith , Jeff Aube , Ranjita S. Betarbet , Juan Botas , Peter J. Brown , Robert R. Butler , Jacob L. Capener , Gregory W. Carter , Gregory A. Cary , Catherine Chen , Rachel Commander , Sabrina Daglish , Suzanne Doolen , Aled M. Edwards , Michelle E. Etoundi , Kevin J. Frankowski , Marta Glavatshikh , Jake Gockley , Katerina Gospodinova , Anna K. Greenwood , Peter A. Greer , Lea T. Grinberg , Shiva Guduru , Levon Halabelian , Crystal Han , Brian Hardy , Laura M. Heath , Stephanie Howell , Suman Jayadev , Stephen Keegan , May Khanna , Dmitri Kireev , Carl Laflamme , Karina Leal , Tom V. Lee , Qianjin Li , David Li-Kroeger , Zhandong Liu , Benjamin A. Logsdon , Frank M. Longo , Lara M. Mangravite , Peter S. Mcpherson , Richard M. Nwakamma , Carolyn A. Paisie , Arti Parihar , Min Qui , Stacey J. Sukoff Rizzo , Karolina A. Rygiel , Julie Schumacher , David D. Scott , Nicholas T. Seyfried , Joshua M. Shulman , Ben Siciliano , Nathaniel Smith , Michael Stashko , Judith A. Tello Vega , Dilipkumar Uredi , Dongxue Wang , Jianjun Wang , Xiaodong Wang , Zhexing Wen , Jesse C. Wiley , Alexander Wilkes , Charles A. Williams , Timothy M. Willson , Aliza Wingo , Thomas S. Wingo , Novak Yang , Jessica E. Young , Miao Yu , Elizabeth L. Zoeller Journal Of Biological Chemistry 20 DOI: 10.1016/j.jbc.2023.105382 Diamond Proposal Number(s): [19301, 19301] Open Access	Oct 2023
	Target 2035 – update on the quest for a probe for every protein Susanne Müller , Suzanne Ackloo , Arij Al Chawaf , Bissan Al-Lazikani , Albert Antolin , Jonathan B. Baell , Hartmut Beck , Shaunna Beedie , Ulrich A. K. Betz , Gustavo Arruda Bezerra , Paul E. Brennan , David Brown , Peter J. Brown , Alex N. Bullock , Adrian J. Carter , Apirat Chaikuad , Mathilde Chaineau , Alessio Ciulli , Ian Collins , Jan Dreher , David Drewry , Kristina Edfeldt , Aled M. Edwards , Ursula Egner , Stephen V. Frye , Stephen M. Fuchs , Matthew D. Hall , Ingo V. Hartung , Alexander Hillisch , Stephen H. Hitchcock , Evert Homan , Natarajan Kannan , James R. Kiefer , Stefan Knapp , Milka Kostic , Stefan Kubicek , Andrew S. Leach , Sven Lindemann , Brian D. Marsden , Hisanori Matsui , Jordan L. Meier , Daniel Merk , Maurice Michel , Maxwell R. Morgan , Anke Mueller-Fahrnow , Dafydd R. Owen , Benjamin G. Perry , Saul H. Rosenberg , Kumar Singh Saikatendu , Matthieu Schapira , Cora Scholten , Sujata Sharma , Anton Simeonov , Michael Sundström , Giulio Superti-Furga , Matthew H. Todd , Claudia Tredup , Masoud Vedadi , Frank Von Delft , Timothy M. Willson , Georg E. Winter , Paul Workman , Cheryl H. Arrowsmith Rsc Medicinal Chemistry 17 DOI: 10.1039/D1MD00228G Open Access Show Abstract ▼ Abstract: Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.	Dec 2021
I03-Macromolecular Crystallography	Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes Benjamin J. Eduful , Sean N. O'Byrne , Louisa Temme , Christopher R. M. Asquith , Yi Liang , Alfredo Picado , Joseph R. Pilotte , Mohammad Anwar Hossain , Carrow I. Wells , William J. Zuercher , Carolina M. C. Catta-Preta , Priscila Zonzini Ramos , André De S. Santiago , Rafael M. Counago , Christopher G. Langendorf , Kévin Nay , Jonathan S. Oakhill , Thomas L. Pulliam , Chenchu Lin , Dominik Awad , Timothy M. Willson , Daniel E. Frigo , John W. Scott , David H. Drewry Journal Of Medicinal Chemistry 8 DOI: 10.1021/acs.jmedchem.0c02274 Diamond Proposal Number(s): [10619] Open Access Show Abstract ▼ Abstract: CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency in vitro, while compounds 13g and 45 had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.	Jul 2021
I02-Macromolecular Crystallography	A chemical probe for dark kinase Stk17b derives its potency and high selectivity through a unique P-Loop conformation Alfredo Picado , Apirat Chaikuad , Carrow I. Wells , Safal Shrestha , William J. Zuercher , Julie E. Pickett , Frank E. Kwarcinski , Parvathi Sinha , Chandi S. De Silva , Reena Zutshi , Shubin Liu , Natarajan Kannan , Stefan Knapp , David H. Drewry , Timothy M. Willson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01174 Diamond Proposal Number(s): [442] Show Abstract ▼ Abstract: STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.	Nov 2020
I03-Macromolecular Crystallography	A chemical probe targeting AAK1 and BMP2K Carrow Wells , Rafael M. Counago , Juanita C. Limas , Tuanny L. Almeida , Jeanette Gowen Cook , David H Drewry , Jonathan M. Elkins , Opher Gileadi , Nirav R. Kapadia , Alvaro Lorente-Macias , Julie E. Pickett , Alexander Riemen , Roberta R. Ruela-De-Sousa , Timothy M. Willson , Cunyu Zhang , William J Zuercher , Reena Zutshi , Alison D. Axtman Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.9b00399 Diamond Proposal Number(s): [14664] Show Abstract ▼ Abstract: Inhibitors based on a 3-acylaminoindazole scaffold were synthesized to yield potent dual AAK1/BMP2K inhibitors. Optimization furnished a small molecule chemical probe (SGC-AAK1-1, 25) that is potent and selective for AAK1/BMP2K over other NAK family members, demonstrates narrow activity in a kinome-wide screen, and is functionally active in cells. This inhibitor represents one of the best available small molecule tools to study the functions of AAK1 and BMP2K.	Oct 2019
I02-Macromolecular Crystallography	WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop Megan J. Agajanian , Matthew P. Walker , Alison D. Axtman , Roberta R. Ruela-De-Sousa , D. Stephen Serafin , Alex D. Rabinowitz , David M. Graham , Meagan B. Ryan , Tigist Tamir , Yuko Nakamichi , Melissa V. Gammons , James M. Bennett , Rafael M. Counago , David H. Drewry , Jonathan M. Elkins , Carina Gileadi , Opher Gileadi , Paulo H. Godoi , Nirav Kapadia , Susanne Müller , André S. Santiago , Fiona J. Sorrell , Carrow I. Wells , Oleg Fedorov , Timothy M. Willson , William J. Zuercher , Michael B. Major Cell Reports 26, 79 - 93.e8 DOI: 10.1016/j.celrep.2018.12.023 Open Access Show Abstract ▼ Abstract: β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity.	Jan 2019
I03-Macromolecular Crystallography	1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors Christopher Asquith , Paulo Godoi , Rafael M. Counago , Tuomo Laitinen , John W. Scott , Christopher Langendorf , Jonathan S. Oakhill , David Drewry , William Zuercher , Panayiotis Koutentis , Timothy Willson , Andreas Kalogirou Molecules 23 DOI: 10.3390/molecules23051221 Diamond Proposal Number(s): [14664] Open Access Show Abstract ▼ Abstract: We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.	May 2018

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