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23 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Discovery and optimization of pyrazine carboxamide AZ3246, a selective HPK1 inhibitor Jason D. Shields , David Baker , Amber Y. S. Balazs , Gayathri Bommakanti , Robert Casella , Shenggen Cao , Steve Cook , Randolph A. Escobar , Stephen Fawell , Francis D. Gibbons , Kathryn A. Giblin , Frederick W. Goldberg , Eric Gosselin , Tyler Grebe , Niresh Hariparsad , Holia Hatoum-Mokdad , Rachel Howells , Samantha J. Hughes , Anne Jackson , Iswarya Karapa Reddy , Jason G. Kettle , Gillian M. Lamont , Scott Lamont , Min Li , Sten O. Nilsson Lill , Deanna A. Mele , Anthony J. Metrano , Adelphe M. Mfuh , Lucas A. Morrill , Bo Peng , Alexander Pflug , Theresa A. Proia , Hadi Rezaei , Ryan Richards , Magdalena Richter , Kevin J. Robbins , Maryann San Martin , Marianne Schimpl , Alwin G. Schuller , Li Sha , Minhui Shen , James E. Sheppeck , Meha Singh , Stephen Stokes , Kun Song , Yuanyuan Sun , Haoran Tang , David J. Wagner , Jianyan Wang , Yanjun Wang , David M. Wilson , Allan Wu , Chengyan Wu , Dedong Wu , Ye Wu , Kevin Xu , Yue Yang , Tieguang Yao , Minwei Ye , Andrew X. Zhang , Hui Zhang , Xiang Zhai , Yanxiao Zhou , Robert E. Ziegler , Neil P. Grimster Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c02631 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.	Feb 2025
I04-Macromolecular Crystallography	Development of D-box peptides to inhibit the anaphase promoting complex/cyclosome Rohan Eapen , Cynthia Okoye , Christopher Stubbs , Marianne Schimpl , Thomas Tischer , Eileen Mccall , Maria Zacharopoulou , Fernando Ferrer , David Barford , David Spring , Cath Lindon , Christopher Phillips , Laura S. Itzhaki Elife DOI: 10.7554/eLife.104238 Diamond Proposal Number(s): [20015] Open Access Show Abstract ▼ Abstract: E3 ubiquitin ligases engage their substrates via ‘degrons’ - short linear motifs typically located within intrinsically disordered regions of substrates. As these enzymes are large, multi-subunit complexes that generally lack natural small-molecule ligands and are hard to drug via conventional means, alternative strategies are needed to target them in diseases, and peptide-based inhibitors derived from degrons represent a promising approach. Here we explore peptide inhibitors of Cdc20, a substrate-recognition subunit and activator of the E3 ubiquitin ligase the anaphase promoting complex/cyclosome (APC/C) that is essential in mitosis and consequently of interest as an anti-cancer target. APC/C engages substrates via degrons that include the ‘Destruction box’ (D-box) motif. We used a rational design approach to construct binders containing unnatural amino acids aimed at better filling a hydrophobic pocket on the surface of Cdc20. We confirmed binding by thermal-shift assays and surface plasmon resonance and determined the structures of a number of the Cdc20-peptide complexes. Using a cellular thermal shift assay we confirmed that the D-box peptides also bind to and stabilise Cdc20 in the cell. We found that the D-box peptides inhibit ubiquitination activity of APC/CCdc20 and are more potent than the small molecule inhibitor Apcin. Lastly, these peptides function as portable degrons capable of driving the degradation of a fused fluorescent protein. Interestingly, we find that although inhibitory activity of the peptides correlates with Cdc20-binding affinity, degradation efficacy does not, which may be due to the complex nature of APC/C regulation and effects of degron binding of subunit recruitment and conformational changes. Our study lays the groundwork for the further development of these peptides as molecular therapeutics for blocking APC/C as well as potentially also for harnessing APC/C for targeted protein degradation.	Jan 2025
I03-Macromolecular Crystallography	Discovery of 6-fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-penetrant, PARP1-selective inhibitor Jeffrey W. Johannes , Amber Y. S. Balazs , Derek Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin J. Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie J. B. Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Lisa Mcwilliams , Mark J. O’connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andy Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01725 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.	Dec 2024
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Accelerated discovery of carbamate Cbl-b Inhibitors using generative AI models and structure-based drug design Taylor R. Quinn , Kathryn A. Giblin , Clare Thomson , Jeffrey A. Boerth , Gayathri Bommakanti , Erin Braybrooke , Christina Chan , Alex J. Chinn , Erin Code , Caifeng Cui , Yukai Fan , Neil P. Grimster , Keishi Kohara , Michelle L. Lamb , Lina Ma , Adelphe M. Mfuh , Graeme R. Robb , Kevin J. Robbins , Marianne Schimpl , Haoran Tang , Jamie Ware , Gail L. Wrigley , Lin Xue , Yun Zhang , Huimin Zhu , Samantha J. Hughes Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01034 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the “Design” phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.	Aug 2024
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Development of a series of pyrrolopyridone MAT2A inhibitors Stephen J. Atkinson , Sharan K. Bagal , Argyrides Argyrou , Sean Askin , Tony Cheung , Elisabetta Chiarparin , Muireann Coen , Iain T. Collie , Ian L. Dale , Claudia De Fusco , Keith Dillman , Laura Evans , Lyman J. Feron , Alison J. Foster , Michael Grondine , Vasudev Kantae , Gillian M. Lamont , Scott Lamont , James T. Lynch , Sten Nilsson Lill , Graeme R. Robb , Jamal Saeh , Marianne Schimpl , James S. Scott , James Smith , Bharath Srinivasan , Sharon Tentarelli , Mercedes Vazquez-Chantada , David Wagner , Jarrod J. Walsh , David Watson , Beth Williamson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c01860 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.	Mar 2024
I04-Macromolecular Crystallography	Discovery, optimization, and biological evaluation of arylpyridones as Cbl-b inhibitors Adelphe M. Mfuh , Jeffrey A. Boerth , Gayathri Bommakanti , Christina Chan , Alex J. Chinn , Erin Code , Patrick J. Fricke , Kathryn A. Giblin , Andrea Gohlke , Catherine Hansel , Niresh Hariparsad , Samantha J. Hughes , Meizhong Jin , Vasudev Kantae , Stefan L. Kavanagh , Michelle L. Lamb , Jordan Lane , Rachel Moore , Taranee Puri , Taylor R. Quinn , Iswarya Reddy , Graeme R. Robb , Kevin J. Robbins , Miguel Gancedo Rodrigo , Marianne Schimpl , Baljinder Singh , Meha Singh , Haoran Tang , Clare Thomson , Jarrod J. Walsh , Jamie Ware , Iain D. G. Watson , Min-Wei Ye , Gail L. Wrigley , Andrew X. Zhang , Yun Zhang , Neil P. Grimster Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c02083 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.	Jan 2024
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Discovery of a novel benzodiazepine series of Cbl-b inhibitors for the enhancement of antitumor immunity Jeffrey A. Boerth , Alex J. Chinn , Marianne Schimpl , Gayathri Bommakanti , Christina Chan , Erin L. Code , Kathryn A. Giblin , Andrea Gohlke , Catherine S. Hansel , Meizhong Jin , Stefan L. Kavanagh , Michelle L. Lamb , Jordan S. Lane , Carrie J. B. Larner , Adelphe M. Mfuh , Rachel K. Moore , Taranee Puri , Taylor R. Quinn , Minwei Ye , Kevin J. Robbins , Miguel Gancedo-Rodrigo , Haoran Tang , Jarrod Walsh , Jamie Ware , Gail L. Wrigley , Iswarya Karapa Reddy , Yun Zhang , Neil P. Grimster Acs Medicinal Chemistry Letters 10 DOI: 10.1021/acsmedchemlett.3c00439 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.	Nov 2023
I03-Macromolecular Crystallography	Optimization of hERG and pharmacokinetic properties for basic dihydro-8H-purin-8-one inhibitors of DNA-PK Frederick W. Goldberg , Attilla K. T. Ting , David Beattie , Gillian M. Lamont , Charlene Fallan , M. Raymond V. Finlay , Beth Williamson , Marianne Schimpl , Alexander R. Harmer , Oladipupo B. Adeyemi , Pär Nordell , Anna S. Cronin , Mercedes Vazquez-Chantada , Derek Barratt , Antonio Ramos-Montoya , Elaine B. Cadogan , Barry R. Davies Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.2c00172 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10–15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pKa, to identify compound 18, which combines low hERG activity (IC50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.	Jul 2022
I03-Macromolecular Crystallography	Optimization of an imidazo[1,2-a]pyridine series to afford highly selective type i1/2 dual Mer/Axl kinase inhibitors with in vivo efficacy William Mccoull , Scott Boyd , Martin R. Brown , Muireann Coen , Olga Collingwood , Nichola L. Davies , Ann Doherty , Gary Fairley , Kristin Goldberg , Elizabeth Hardaker , Guang He , Edward J. Hennessy , Philip Hopcroft , George Hodgson , Anne Jackson , Xiefeng Jiang , Ankur Karmokar , Anne-Laure Lainé , Nicola Lindsay , Yumeng Mao , Roshini Markandu , Lindsay Mcmurray , Neville Mclean , Lorraine Mooney , Helen Musgrove , J. Willem M. Nissink , Alexander Pflug , Venkatesh Pilla Reddy , Philip B. Rawlins , Emma Rivers , Marianne Schimpl , Graham F. Smith , Sharon Tentarelli , Jon Travers , Robert I. Troup , Josephine Walton , Cheng Wang , Stephen Wilkinson , Beth Williamson , Jon Winter-Holt , Dejian Yang , Yuting Zheng , Qianxiu Zhu , Paul D. Smith Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00920 Diamond Proposal Number(s): [17180] Show Abstract ▼ Abstract: Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.	Sep 2021
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs Jeffrey W. Johannes , Amber Balazs , Derek Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Scott Martin , Lisa Mcwilliams , Mark J. O'Connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andrew Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01012 Diamond Proposal Number(s): [14631, 17180, 20015] Show Abstract ▼ Abstract: Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.	Sep 2021

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