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Instruments / Technical Area	Publication Details	Published
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
I04-Macromolecular Crystallography	Crystal structure and inhibitor identifications reveal targeting opportunity for the atypical MAPK kinase ERK3 Martin Schroeder , Panagis Filippakopoulos , Martin P. Schwalm , Carla A. Ferrer , David H. Drewry , Stefan Knapp , Apirat Chaikuad International Journal Of Molecular Sciences 21 DOI: 10.3390/ijms21217953 Diamond Proposal Number(s): [105433] Open Access Show Abstract ▼ Abstract: Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase.	Nov 2020
I24-Microfocus Macromolecular Crystallography	Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors Gerson S. Profeta , Caio V. Dos Reis , André Da S. Santiago , Paulo H. C. Godoi , Angela M. Fala , Carrow I. Wells , Roger Sartori , Anita P. T. Salmazo , Priscila Z. Ramos , Katlin B. Massirer , Jonathan M. Elkins , David H. Drewry , Opher Gileadi , Rafael M. Counago Scientific Reports 9 DOI: 10.1038/s41598-019-52795-1 Diamond Proposal Number(s): [16171] Open Access Show Abstract ▼ Abstract: Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this protein kinase. Moreover, CAMKK2 and its closest human homolog, CAMKK1, are thought to have overlapping biological roles. Here we present six new co-structures of potent ligands bound to CAMKK2 identified from a library of commercially-available kinase inhibitors. Enzyme assays confirmed that most of these compounds are equipotent inhibitors of both human CAMKKs and isothermal titration calorimetry (ITC) revealed that binding to some of these molecules to CAMKK2 is enthalpy driven. We expect our results to advance current efforts to discover small molecule kinase inhibitors selective to each human CAMKK.	Nov 2019
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
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Comprehensive characterization of the Published Kinase Inhibitor Set Jonathan M Elkins , Vita Fedele , Marta Szklarz , Kamal R Abdul Azeez , Eidarus Salah , Jowita Mikolajczyk , Sergei Romanov , Nikolai Sepetov , Xi-ping Huang , Bryan L Roth , Ayman Al Haj Zen , Denis Fourches , Eugene Muratov , Alex Tropsha , Joel Morris , Beverly A Teicher , Mark Kunkel , David H Drewry , William J Zuercher , Stefan Knapp Nature Biotechnology DOI: 10.1038/nbt.3374 PMID: 26501955 Show Abstract ▼ Abstract: Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein–coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.	Oct 2015
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition Natalie H. Theodoulou , Paul Bamborough , Andrew J. Bannister , Isabelle Becher , Rino A. Bit , Ka Hing Che , Chun-wa Chung , Antje Dittmann , Gerard Drewes , David H. Drewry , Laurie Gordon , Paola Grandi , Melanie Leveridge , Matthew Lindon , Anne-marie Michon , Judit Molnar , Samuel C. Robson , Nicholas C. O. Tomkinson , Tony Kouzarides , Phillips G. Humphreys Journal Of Medicinal Chemistry 27 (8) DOI: 10.1021/acs.jmedchem.5b00256 PMID: 25856009 Open Access Show Abstract ▼ Abstract: Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.	Apr 2015

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