Journal of Medicinal Chemistry (J Med Chem)

Publications in this journal

• Article: Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease.

  Yutong Jiang, Steven W Andrews, Kevin Condroski, Brad Buckman, Vlad Serebryany, Steve Wenglowsky, April Kennedey, Machender Madduru, Bin Wang, Michael Lyon, [......], Mary Geck Do, Hailong Zhang, Joshua A Ballard, Guy Vigers, Barbra Brandhuber, Peter Stengel, John Josey, Leonid Beigelman, Lawrence Blatt, Scott D Seiwert
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  ABSTRACT: HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication, but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed sub-nanomolar potency against the NS3 protease in a sub-genomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains, and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
  Journal of Medicinal Chemistry 05/2013;
• Article: Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase.

  Andrew Maynard, Renae M Crosby, Byron Ellis, Robert Hamatake, Zhi Hong, Brian A Johns, Kirsten M Kahler, Cecilia Koble, Anna L Leivers, Martin R Leivers, [......], Christian Voitenleitner, Jill T Walker, Greg Waitt, Jason Weatherhead, Kurt L Weaver, Shawn Williams, Lois Wright, Zhiping Z Xiong, David Haigh, J Brad Shotwell
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  ABSTRACT: A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
  Journal of Medicinal Chemistry 05/2013;
• Article: Lead Optimization of a 4-Aminopyridine Benzamide Scaffold to Identify Potent, Selective and Orally Bioavailable TYK2 Inhibitors.

  Jun Liang, Anne van Abbema, Mercedesz Balazs, Kathy Barret, Leo Berezhkovskiy, Wade Blair, Christine Chang, Donnie Delarosa, Jason Devoss, Jim Driscoll, [......], Sue Sohn, Vickie Tsui, Mark Ultsch, Lawren C Wu, Yisong Xiao, Wenqian Yang, Judy Young, Birong Zhang, Bing-Yan Zhu, Steven Magnuson
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  ABSTRACT: Herein we report our lead optimization effort to identify potent, selective and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1- and JAK2-selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1- and JAK2-selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-gamma (IFN, suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
  Journal of Medicinal Chemistry 05/2013;
• Article: Fragment based ligand design of novel potent inhibitors of Tankyrases.

  Erik Andreas Larsson, Anna Jansson, Fui Mee Ng, Siew Wen Then, Resmi Panicker, Boping Liu, Kanda Sangthongpitag, Vishal Pendharkar, Shi Jing Tai, Jeffrey Hill, Chen Dan, Soo Yei Ho, Wei Wen Cheong, Anders Poulsen, Stephanie Blanchard, Grace Ruiting Lin, Jenefer Alam, Thomas H Keller, Pär Nordlund
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  ABSTRACT: Tankyrases constitute potential drug targets for cancer and myelin degrading diseases. We have applied a structure and biophysics driven fragment based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide -binding site, a local hot spot for fragment binding. Evolution of the fragment hit, 4-methyl-1,2-dihydroquinolin-2-one (2), along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinoline-2(1H)-one (11) reveals that the non-planar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other PARP family members. A further cycle of optimisation yielded compounds with affinities and IC50's in the low nM range and with good solubility, PARP-selectivity and ligand efficiency.
  Journal of Medicinal Chemistry 05/2013;
• Article: Contributions of Academic Labs to the Discovery and Development of Chemical Biology Tools.

  Donna M Huryn, Lynn O Resnick, Peter Wipf
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  ABSTRACT: The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools, while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is not apparent are ideally suited to be pursued in a university setting. In this perspective, we highlight five projects that emanated from academic research groups and generated valuable tool compounds that have been used to interrogate biological phenomena: Reactive oxygen species (ROS) sensors, GPR30 agonists and antagonists, selective CB2 agonists, Hsp70 modulators and beta-amyloid PET imaging agents. By continuing to take advantage of the unique expertise resident in university settings, and the ability to pursue novel projects that may have great scientific value, but limited or no immediate commercial value, probes from academic research groups continue to provide useful tools and generate a long-term resource for biomedical researchers.
  Journal of Medicinal Chemistry 05/2013;
• Article: Discovery of the First Histone Deacetylase 6/8 Dual Inhibitor.

  David E Olson, Florence F Wagner, Taner Kaya, Jennifer P Gale, Nadia Aidoud, Emeline L Davoine, Fanny Lazzaro, Michel Weiwer, Yan-Ling Zhang, Edward B Holson
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  ABSTRACT: We disclose the first small molecule histone deacetylase (HDAC) inhibitor (3, BRD73954) capable of potently and selectively inhibiting both HDAC6 and HDAC8 despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our data demonstrate that meta substituents of phenyl hydroxamic acids are readily accommodated upon binding to HDAC6, and furthermore, are necessary for the potent inhibition of HDAC8.
  Journal of Medicinal Chemistry 05/2013;
• Article: Bispyrimidines as potent histamine H4 receptor ligands: delineation of structure activity relationships and detailed H4 receptor binding mode.

  Harald Engelhardt, Sabine Schultes, Chris de Graaf, Saskia Nijmeijer, Henry F Vischer, Obbe P Zuiderveld, Julia Dobler, Katharina Stachurski, Moriz Mayer, Heribert Arnhof, Dirk Scharn, Eric E J Haaksma, Iwan J P de Esch, Rob Leurs
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  ABSTRACT: The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g. indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific.
  Journal of Medicinal Chemistry 05/2013;
• Article: Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5'-Monophosphate Dehydrogenase.

  Suresh Kumar Gorla, Mandapati Kavitha, Minjia Zhang, James En Wai Chin, Xiaoping Liu, Boris Striepen, Magdalena Makowska-Grzyska, Youngchang Kim, Andrzej Joachimiak, Lizbeth Hedstrom, Gregory D Cuny
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  ABSTRACT: Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5'-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD(+). The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 μM) against a panel of four mammalian cells lines.
  Journal of Medicinal Chemistry 05/2013;
• Article: Novel Hybrids of Phenylsulfonylfuroxan and Anilinopyrimidine as Potent and Selective Epidermal Growth Factor Receptor Inhibitors for Intervention of Non-Small Cell Lung Cancer.

  Chun Han, Zhangjian Huang, Chao Zheng, Ledong Wan, Lianwen Zhang, Sixun Peng, Ke Ding, Hongbin Ji, Jide Tian, Yihua Zhang
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  ABSTRACT: A series of hybrids 12a-k from phenylsulfonylfuroxan and anilinopyrimidine were synthesized and biologically evaluated as EGFR inhibitors for intervention of NSCLC. Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 μM), and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50s of 0.007 and 0.029 μM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002, inhibited EGFR downstream signaling in H1975 cells, and suppressed the NF-κB activation in H1975 cells while WZ4002 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in a H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.
  Journal of Medicinal Chemistry 05/2013;
• Article: Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-sparing phosphoinositide 3-kinase (PI3K) inhibitor with high unbound exposure and robust in vivo anti-tumor activity.

  Chudi Ndubaku, Timothy P Heffron, Steven Thomas Staben, Matthew Baumgardner, Nicole Blaquiere, Erin Bradley, Richard Bull, Steven Do, Jennafer Dotson, Danette Dudley, [......], Jodie Pang, Steve Price, Wei Wei Prior, Laurent Salphati, Steve Sideris, Jeffrey Wallin, Lan Wang, Binqing Wei, Deepak Sampath, Alan G Olivero
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  ABSTRACT: Dysfunctional signaling through the PI3K/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo anti-tumor activity on the free drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under Phase I evaluation as a potential treatment for human malignancies.
  Journal of Medicinal Chemistry 05/2013;
• Article: Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors.

  Fei Yu, Qi Wang, Zhen Zhang, Yi-Yun Peng, Yun-Yan Qiu, Yong-Ying Shi, Yong-Xiang Zheng, Su-Long Xiao, Han Wang, Xiao-Xi Huang, Lingyi Zhu, Kun-Bo Chen, Chuan-Ke Zhao, Chuan-Ling Zhang, Mao-Rong Yu, Di-An Sun, Li-He Zhang, De-Min Zhou
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  ABSTRACT: Development of hepatitis C virus (HCV) entry inhibitors represents an emerging approach that satisfies a tandem mechanism for use with other inhibitors in a multifaceted cocktail. By screening Chinese herbal extracts, oleanolic acid (OA) was found displaying weak potency to inhibit HCV entry with IC50 at 10 μM. Chemical exploration of this triterpene compound revealed its pharmacophore requirement for blocking HCV entry - ring A, B and E are conserved while ring D is tolerant to some modifications. Hydroxylation at C-16 significantly enhanced its potency for inhibiting HCV entry with IC50 at 1.4 μM. Further modification by conjugation of this new lead with a disaccharide at 28-COOH removed the undesired hemolytic effect, and more importantly increased its potency by ~5-fold (54a, IC50 0.3 μM). Formation of a triterpene dimer via a linker bearing triazole (70) dramatically increased its potency with IC50 at ~10 nM. Mechanistically, such functional triterpenes interrupt the interaction between HCV envelope protein E2 and its receptor CD81 via binding to E2, thus blocking virus and host cell recognition. This study establishes the importance of triterpene natural products as new leads for the development of potential HCV entry inhibitors.
  Journal of Medicinal Chemistry 05/2013;
• Article: Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.

  Mark Zak, Christopher A Hurley, Stuart I Ward, Philippe Bergeron, Kathy Barrett, Mercedesz Balazs, Wade S Blair, Richard Bull, Paroma Chakravarty, Christine Chang, [......], Scott Savage, Steven Shia, Micah Steffek, Savita Ubhayakar, Anne Van Abbema, Ignacio Aliagas, Barbara Avitabile-Woo, Yisong Xiao, Jing Yang, Janusz Kulagowski
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  ABSTRACT: Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analog in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms, and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
  Journal of Medicinal Chemistry 05/2013;
• Article: Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.

  Steven J Taylor, Anil K Padyana, Asitha Abeywardane, Shuang Liang, Ming-Hong Hao, Stéphane De Lombaert, John R Proudfoot, Bennett S Farmer, Xiang Li, Brandon Collins, Daniel R Albaugh, Leslie Martin, Melissa Hill-Drzewi, Steven S Pullen, Hidenori Takahashi
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  ABSTRACT: Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-Ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100 fold selective over cathepsin G, and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.
  Journal of Medicinal Chemistry 05/2013;
• Article: Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy.

  Christopher M Bailey, Todd J Sullivan, Pinar Iyidogan, Julian Tirado-Rives, Raymond Chung, Juliana Ruiz-Caro, Ebrahim Mohamed, William Jorgensen, Roger Hunter, Karen S Anderson
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  ABSTRACT: Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.
  Journal of Medicinal Chemistry 05/2013;
• Article: Optimized Chemical Probes for REV-ERB∝

  Ryan Paul Trump, Stefano Bresciani, Anthony W J Cooper, James Tellam, Justyna Wojno, John Blaikley, Lisa A Orband-Miller, Jennifer A Kashatus, Mohamed Boudjelal, Helen C Dawson, Andrew Loudon, David W Ray, Daniel Grant, Stuart N Farrow, Timothy Mark Willson, Nicholas Charles Oliver Tomkinson
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  ABSTRACT: REV-ERB∝ has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERB∝ agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. Potent REV-ERB∝ agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXR∝. Amine 4 demonstrated in vivo bioavailability after either IV or oral dosing.
  Journal of Medicinal Chemistry 05/2013;
• Article: Synthesis, 18F-Radiolabeling and In Vivo Biodistribution Studies of N-Fluorohydroxybutyl Isatin Sulfonamides using Positron Emission Tomography.

  Panupun Limpachayaporn, Stefan Wagner, Klaus Kopka, Sven Hermann, Michael Schäfers, Günter Haufe
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  ABSTRACT: The effector caspases-3 and -7 play a central role in the programmed type-I cell death (apoptosis). Molecular imaging using Positron Emission Tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo- and enantiopure isatin sulfonamide-based potent and selective caspases-3 and -7 inhibitors were prepared by cyclic sulfate ring opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC50 11.8 nM and 0.951 nM), which makes them appropriate PET radiotracer candidates. Therefore, N-(4-[18F]fluoro-(3R)-hydroxybutyl)- and N-(3S)-[18F]fluoro-4-hydroxybutyl)-5-[1-(2S)-methoxymethylpyrrolidinyl)sulfonyl]isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10-127 GBq/μmol using [18F]fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild type mice using PET/CT imaging proved fast clearance of the tracer after tail vein injection.
  Journal of Medicinal Chemistry 05/2013;
• Article: X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor.

  Jonathan M Elkins, Jing Wang, Xianming Deng, Michael J Pattison, Simon Arthur, Tatiana Erazo, Nestor Gomez, Jose M Lizcano, Nathanael S Gray, Stefan Knapp
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  ABSTRACT: The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition as well as angiogenesis. To date no three dimensional structure has been published that would allow rational design of inhibitors. To address this we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, as compared to the related ERKs, p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalised using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.
  Journal of Medicinal Chemistry 05/2013;
• Article: An optimized method of G-protein coupled receptor homology modeling: its application to the discovery of novel CXCR7 ligands.

  Yasushi Yoshikawa, Shinya Oishi, Tatsuhiko Kubo, Noriko Tanahara, Nobutaka Fujii, Toshio Furuya
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  ABSTRACT: Homology modeling of G-protein coupled transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand binding pocket of GPCRs. We have developed an optimized GPCR structure modeling method based on multiple GPCR crystal structures. This method was designed to be applicable to distantly related receptors of known structural templates. CXC chemokine receptor (CXCR7) is a potential drug target for cancer chemotherapy. Homology modeling, docking and virtual screening for CXCR7 were carried out using our method. The predicted docking poses of the known antagonists were different from the crystal structure of human CXCR4 with the small molecule antagonist (IT1t). Furthermore, 21 novel CXCR7 ligands with IC50 values of 1.29-11.4 μM with various scaffolds were identified by the structure-based virtual screening.
  Journal of Medicinal Chemistry 05/2013;
• Article: 1-Phenyl-4-benzoyl-1H-1,2,3-triazoles as Orally Bioavailable Transcriptional Function Suppressors of Estrogen-Related Receptor α

  Shilin Xu, Xiaoxi Zhuang, Xiaofen Pan, Zhang Zhang, Lei Duan, Yingxue Liu, Lianwen Zhang, Xiaomei Ren, Ke Ding
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  ABSTRACT: Estrogen-related receptor α is a potential candidate target for therapeutic treatment of breast cancer. We describe the discovery and structure-activity relationship study of a series of 1-phenyl-4-benzoyl-1H-1,2,3-triazoles as novel suppressors of ERRα transcriptional functions. The most promising compound, 2-aminophenyl-(1-(3-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methan-one (14n) potently suppressed the transcriptional functions of ERRα with IC50 = 0.021 μM in a cell-based reporter gene assay and also decreased both the mRNA levels and the protein levels of ERR and the downstream targets. This compound inhibited the proliferation and migration of breast cancer cells with high level of ERRα. Preliminary pharmacokinetic studies suggested that it possessed a good pharmacokinetic profile with an oral bioavailability of 71.8%. The compounds may serve as novel small molecule probes for further validation of ERRα as a molecular target for anticancer drug development.
  Journal of Medicinal Chemistry 05/2013;