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Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey RJ, Tansey WP, Stauffer SR, Lee T, Fesik SW
(2020) J Med Chem 63: 656-675
MeSH Terms: Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Chromatin, Crystallography, X-Ray, Drug Design, Drug Discovery, Epigenetic Repression, Genes, myc, Humans, Intracellular Signaling Peptides and Proteins, Quinolones, Structure-Activity Relationship, WD40 Repeats
Show Abstract · Added March 3, 2020
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
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16 MeSH Terms
Quantum dots reveal heterogeneous membrane diffusivity and dynamic surface density polarization of dopamine transporter.
Kovtun O, Tomlinson ID, Ferguson RS, Rosenthal SJ
(2019) PLoS One 14: e0225339
MeSH Terms: Algorithms, Animals, Cell Membrane, Dopamine Plasma Membrane Transport Proteins, HEK293 Cells, Humans, Models, Theoretical, Quantum Dots, Reproducibility of Results, Structure-Activity Relationship
Show Abstract · Added March 30, 2020
The presynaptic dopamine transporter mediates rapid reuptake of synaptic dopamine. Although cell surface DAT trafficking recently emerged as an important component of DAT regulation, it has not been systematically investigated. Here, we apply our single quantum dot (Qdot) tracking approach to monitor DAT plasma membrane dynamics in several heterologous expression cell hosts with nanometer localization accuracy. We demonstrate that Qdot-tagged DAT proteins exhibited highly heterogeneous membrane diffusivity dependent on the local membrane topography. We also show that Qdot-tagged DATs were localized away from the flat membrane regions and were dynamically retained in the membrane protrusions and cell edges for the duration of imaging. Single quantum dot tracking of wildtype DAT and its conformation-defective coding variants (R60A and W63A) revealed a significantly accelerated rate of dysfunctional DAT membrane diffusion. We believe our results warrant an in-depth investigation as to whether compromised membrane dynamics is a common feature of brain disorder-derived DAT mutants.
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MeSH Terms
An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders.
Porter JD, Vivas O, Weaver CD, Alsafran A, DiMilo E, Arnold LA, Dickson EJ, Dockendorff C
(2019) Bioorg Med Chem Lett 29: 126681
MeSH Terms: Anthracenes, Dose-Response Relationship, Drug, KCNQ2 Potassium Channel, KCNQ3 Potassium Channel, Mental Disorders, Molecular Structure, Neurodegenerative Diseases, Potassium Channel Blockers, Structure-Activity Relationship
Show Abstract · Added March 27, 2020
A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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9 MeSH Terms
Discovery of a novel 3,4-dimethylcinnoline carboxamide M positive allosteric modulator (PAM) chemotype via scaffold hopping.
Temple KJ, Engers JL, Long MF, Gregro AR, Watson KJ, Chang S, Jenkins MT, Luscombe VB, Rodriguez AL, Niswender CM, Bridges TM, Conn PJ, Engers DW, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 126678
MeSH Terms: Allosteric Regulation, Amides, Azetidines, Benzene, Molecular Structure, Protein Binding, Pyrazines, Pyridines, Pyrimidines, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M PAM activity and improved clearance and protein binding profiles.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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1 Members
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11 MeSH Terms
Upgraded molecular models of the human KCNQ1 potassium channel.
Kuenze G, Duran AM, Woods H, Brewer KR, McDonald EF, Vanoye CG, George AL, Sanders CR, Meiler J
(2019) PLoS One 14: e0220415
MeSH Terms: Humans, Hydrogen Bonding, KCNQ1 Potassium Channel, Lipids, Loss of Function Mutation, Models, Molecular, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, Structure-Activity Relationship
Show Abstract · Added March 21, 2020
The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor-pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction.
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MeSH Terms
Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy.
Yamada Y, Yohn SE, Gilliland K, Loch MT, Schulte ML, Rodriguez AL, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 2670-2674
MeSH Terms: Animals, Anti-Anxiety Agents, Antidepressive Agents, Dose-Response Relationship, Drug, Mice, Molecular Structure, Pyridones, Rats, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes the further optimization of a series of mGlu NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca flux via a promiscuous G protein (G) versus native coupling to GIRK channels), identified both full and partial mGlu NAMs and a new in vivo tool compound, VU6017587. This mGlu NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu affords anxiolytic-like and antidepressant-like phenotypes in mice.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M PAMs.
Chopko TC, Han C, Gregro AR, Engers DW, Felts AS, Poslusney MS, Bollinger KA, Morrison RD, Bubser M, Lamsal A, Luscombe VB, Cho HP, Schnetz-Boutaud NC, Rodriguez AL, Chang S, Daniels JS, Stec DF, Niswender CM, Jones CK, Wood MR, Wood MW, Duggan ME, Brandon NJ, Conn PJ, Bridges TM, Lindsley CW, Melancon BJ
(2019) Bioorg Med Chem Lett 29: 2224-2228
MeSH Terms: Aldehyde Oxidase, Animals, Drug Discovery, Humans, Myotonia Congenita, Rats, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes progress towards an M PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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3 Members
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8 MeSH Terms
VU6005806/AZN-00016130, an advanced M positive allosteric modulator (PAM) profiled as a potential preclinical development candidate.
Engers DW, Melancon BJ, Gregro AR, Bertron JL, Bollinger SR, Felts AS, Konkol LC, Wood MR, Bollinger KA, Luscombe VB, Rodriguez AL, Jones CK, Bubser M, Yohn SE, Wood MW, Brandon NJ, Dugan ME, Niswender CM, Conn PJ, Bridges TM, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 1714-1718
MeSH Terms: Allosteric Regulation, Molecular Structure, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes progress towards an M PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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2 Members
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4 MeSH Terms
BCL::Mol2D-a robust atom environment descriptor for QSAR modeling and lead optimization.
Vu O, Mendenhall J, Altarawy D, Meiler J
(2019) J Comput Aided Mol Des 33: 477-486
MeSH Terms: Algorithms, Drug Design, Drug Discovery, Humans, Ligands, Quantitative Structure-Activity Relationship, Small Molecule Libraries
Show Abstract · Added March 21, 2020
Comparing fragment based molecular fingerprints of drug-like molecules is one of the most robust and frequently used approaches in computer-assisted drug discovery. Molprint2D, a popular atom environment (AE) descriptor, yielded the best enrichment of active compounds across a diverse set of targets in a recent large-scale study. We present here BCL::Mol2D descriptors that outperformed Molprint2D on nine PubChem datasets spanning a wide range of protein classes. Because BCL::Mol2D records the number of AEs from a universal AE library, a novel aspect of BCL::Mol2D over the Molprint2D is its reversibility. This property enables decomposition of prediction from machine learning models to particular molecular substructures. Artificial neural networks with dropout, when trained on BCL::Mol2D descriptors outperform those trained on Molprint2D descriptors by up to 26% in logAUC metric. When combined with the Reduced Short Range descriptor set, our previously published set of descriptors optimized for QSARs, BCL::Mol2D yields a modest improvement. Finally, we demonstrate how the reversibility of BCL::Mol2D enables visualization of a 'pharmacophore map' that could guide lead optimization for serine/threonine kinase 33 inhibitors.
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7 MeSH Terms
Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.
Lee T, Christov PP, Shaw S, Tarr JC, Zhao B, Veerasamy N, Jeon KO, Mills JJ, Bian Z, Sensintaffar JL, Arnold AL, Fogarty SA, Perry E, Ramsey HE, Cook RS, Hollingshead M, Davis Millin M, Lee KM, Koss B, Budhraja A, Opferman JT, Kim K, Arteaga CL, Moore WJ, Olejniczak ET, Savona MR, Fesik SW
(2019) J Med Chem 62: 3971-3988
MeSH Terms: Animals, Antineoplastic Agents, Azepines, Binding Sites, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Drug Evaluation, Preclinical, Female, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Dynamics Simulation, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Protein Structure, Tertiary, Small Molecule Libraries, Structure-Activity Relationship, Xenograft Model Antitumor Assays
Show Abstract · Added April 15, 2019
Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.
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20 MeSH Terms