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164 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
	A qualified success: discovery of a new series of ATAD2 bromodomain inhibitors with a novel binding mode using high-throughput screening and hit qualification Paul Bamborough , Chun-wa Chung , Emmanuel H. Demont , Angela M. Bridges , Peter D. Craggs , David P. Dixon , Peter Francis , Rebecca C. Furze , Paola Grandi , Emma J. Jones , Bhumika Karamshi , Kelly Locke , Simon C. C. Lucas , Anne-marie Michon , Darren J. Mitchell , Peter Pogány , Rab K. Prinjha , Christina Rau , Ana Maria Roa , Andrew D. Roberts , Robert J. Sheppard , Robert J. Watson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00673 Show Abstract ▼ Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure–activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.	Aug 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity Zoltan Szlávik , Levente Ondi , Márton Csékei , Attila Paczal , Zoltán B. Szabó , Gábor Radics , James Murray , James Davidson , Ijen Chen , Ben Davis , Roderick E. Hubbard , Christopher Pedder , Pawel Dokurno , Allan Surgenor , Julia Smith , Alan Robertson , Gaetane Letoumelin-braizat , Nicolas Cauquil , Marion Zarka , Didier Demarles , Francoise Perron-sierra , Audrey Claperon , Frederic Colland , Olivier Geneste , András Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00134 Diamond Proposal Number(s): [17182, 1194, 2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.	Jul 2019
I04-Macromolecular Crystallography	Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) Yan Xiong , Holger Greschik , Catrine Johansson , Ludwig Seifert , Johannes Bacher , Kwang-su Park , Nicolas Babault , Michael L. Martini , Vincent Fagan , Fengling Li , Irene Chau , Thomas Christott , David Dilworth , Dalia Barsyte-lovejoy , Masoud Vedadi , Cheryl H. Arrowsmith , Paul E. Brennan , Oleg Fedorov , Manfred Jung , Gillian Farnie , Jing Liu , Udo C. T. Oppermann , Roland Schüle , Jian Jin Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00522 Show Abstract ▼ Abstract: By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (Spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to non-tumorigenic cells. The crystal structure of the SPIN1–compound 3 complex indicated that it selectively binds Tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective and cell-active fragment-like inhibitors can be generated by targeting a single Tudor domain.	Jul 2019
I04-Macromolecular Crystallography	2-amino-2, 3-dihydro-1h-indene-5-carboxamide-based discoidin domain receptors 1 (DDR1) inhibitors: design, synthesis, and in vivo anti-pancreatic cancer efficacy Dongsheng Zhu , Huocong Huang , Daniel Pinkas , Jinfeng Luo , Debolina Ganguly , Alice E. Fox , Emily Arner , Qiuping Xiang , Zheng-chao Tu , Alex N. Bullock , Rolf A Brekken , Ke Ding , Xiaoyun Lu Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00365 Diamond Proposal Number(s): [15433] Show Abstract ▼ Abstract: Pancreatic cancer is a leading cause of cancer-related death. A series of 2-amino-2, 3-dihydro-1H-indene-5-carboxamide derivatives were designed and synthesized as novel selective DDR1 inhibitors to exhibit promising in vitro and in vivo anti-pancreatic cancer activity. One of the representative compounds, 7f, binds with DDR1 with a Kd value of 5.9 nM and suppresses the kinase activity with an IC50 value of 14.9 nM, but is significantly less potent for majority of a panel of 403 wild-type kinases. The compound potently inhibited collagen-induced epithelial-mesenchymal transition (EMT) and dose-dependently suppressed colony formation of pancreatic cancer cells. Furthermore, 7f also demonstrated reasonable pharmacokinetic profiles and displayed promising in vivo therapeutic efficacy in an orthotopic mouse model of pancreatic cancer. Compound 7f may serve as a new lead compound for future drug discovery.	Jul 2019
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Development of inhibitors against Mycobacterium abscessus tRNA (m 1 G37) methyltransferase (TrmD) using fragment-based approaches Andrew J. Whitehouse , Sherine E. Thomas , Karen P. Brown , Alexander Fanourakis , Daniel S.-h. Chan , M. Daben J. Libardo , Vitor Mendes , Helena I. M. Boshoff , R. Andres Floto , Chris Abell , Tom Blundell , Anthony G. Coyne Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00809 Diamond Proposal Number(s): [9537, 14043, 18548] Open Access Show Abstract ▼ Abstract: Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.	Jul 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of a first-in-class Receptor Interacting Protein 2 (RIP2) kinase specific clinical candidate, 2-((4-(Benzo[ d ]thiazol-5-ylamino)-6-( tert -butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate, for the treatment of inflammatory diseases Pamela A. Haile , Linda N. Casillas , Bartholomew J. Votta , Gren Z. Wang , Adam K. Charnley , Xiaoyang Dong , Michael J. Bury , Joseph J. Romano , John F. Mehlmann , Bryan W. King , Karl F. Erhard , Charles R. Hanning , David B. Lipshutz , Biva M. Desai , Carol A. Capriotti , Michelle C. Schaeffer , Scott B. Berger , Mukesh K. Mahajan , Michael A. Reilly , Rakesh Nagilla , Elizabeth J. Rivera , Helen H. Sun , John K. Kenna , Allison M. Beal , Michael T. Ouellette , Mike Kelly , Gillian Stemp , Máire A. Convery , Anna Vossenkämper , Thomas T. Macdonald , Peter J. Gough , John Bertin , Robert W. Marquis Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00575 Diamond Proposal Number(s): [1195, 5799] Show Abstract ▼ Abstract: RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.	Jul 2019
I02-Macromolecular Crystallography	Synthesis and structure–activity relationships of 3,5-disubstituted-pyrrolo[2,3- b ]pyridines as inhibitors of adaptor-associated kinase 1 with antiviral activity Sven Verdonck , Szu-yuan Pu , Fiona J. Sorrell , Jon M. Elkins , Mathy Froeyen , Ling-jie Gao , Laura I. Prugar , Danielle E. Dorosky , Jennifer M. Brannan , Rina Barouch-bentov , Stefan Knapp , John M. Dye , Piet Herdewijn , Shirit Einav , Steven De Jonghe Journal Of Medicinal Chemistry 62, 5810 - 5831 DOI: 10.1021/acs.jmedchem.9b00136 Diamond Proposal Number(s): [10619] Show Abstract ▼ Abstract: There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine–threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3-b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.	May 2019
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4 Stephanie Myers , Duncan C. Miller , Lauren Molyneux , Mercedes Arasta , Ruth H. Bawn , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Tim Hammonds , Ian R. Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , David R. Newell , Paul J. Owen , Leon C. Pang , Tristan Reuillon , Laurent J. M. Rigoreau , Huw Thomas , Julie A. Tucker , Lan-zhen Wang , Ai-ching Wong , Martin E. M. Noble , Stephen R. Wedge , Celine Cano European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.057 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 μM for ERK5; IC50 > 120 μM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.	May 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays Yann-vai Le Bihan , Rachel M. Lanigan , Butrus Atrash , Mark G. Mclaughlin , Srikannathasan Velupillai , Andrew G. Malcolm , Katherine S. England , Gian Filippo Ruda , N. Yi Mok , Anthony Tumber , Kathy Tomlin , Harry Saville , Erald Shehu , Craig Mcandrew , Leanne Carmichael , James M. Bennett , Fiona Jeganathan , Paul Eve , Adam Donovan , Angela Hayes , Francesca Wood , Florence I. Raynaud , Oleg Fedorov , Paul Brennan , Rosemary Burke , Rob Van Montfort , Olivia W. Rossanese , Julian Blagg , Vassilios Bavetsias European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.041 Diamond Proposal Number(s): [20145] Open Access Show Abstract ▼ Abstract: Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, the conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggest that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.	May 2019
I02-Macromolecular Crystallography	Discovery and lead-optimization of 4,5-dihydropyrazoles as mono-kinase selective, orally bioavailable and efficacious inhibitors of receptor interacting protein 1 (RIP1) kinase Philip A. Harris , Nicolas Faucher , Nicolas George , Patrick M Eidam , Bryan W. King , Gemma White , Niall A Anderson , Deepak Bandyopadhyay , Allison M. Beal , Veronique Beneton , Scott B. Berger , Nino Campobasso , Sebastien Campos , Carol A. Capriotti , Julie A. Cox , Alain Daugan , Frederic Donche , Marie-helene Fouchet , Joshua N. Finger , Brad Geddes , Peter J. Gough , Pascal Grondin , Bonnie Hoffman , Sandra J. Hoffman , Susan Hutchinson , Jae U. Jeong , Emilie Jigorel , Pauline Lamoureux , Lara K Leister , John D. Lich , Mukesh K. Mahajan , Jamel Meslamani , Julie E. Mosley , Rakesh Nagilla , Pamela Nassau , Sze-ling Ng , Michael T. Ouellette , Kishore Pasikanti , Florent Potvain , Michael A. Reilly , Elizabeth J. Rivera , Stephane Sautet , Michelle C. Schaeffer , Clark A. Sehon , Helen H. Sun , James H. Thorpe , Rachel D. Totoritis , Paris Ward , Natalie Wellaway , David D. Wisnoski , James M. Woolven , John Bertin , Robert W. Marquis Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00318 Diamond Proposal Number(s): [12779] Show Abstract ▼ Abstract: RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis and ulcerative colitis, and neuro-logical diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. In this paper we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.	Apr 2019

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