Now showing items 1-20 of 32

    • A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells 

      Duan, Zhenfeng; Zhang, Jianming; Ye, Shunan; Shen, Jacson; Choy, Edwin; Cote, Gregory; Harmon, David; Mankin, Henry; Hua, Yingqi; Zhang, Yu; Gray, Nathanael S; Hornicek, Francis J (BioMed Central, 2014)
      Background: Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR ...
    • Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer 

      Terai, Hideki; Tan, Li; Beauchamp, Ellen M.; Hatcher, John M.; Liu, Qingsong; Meyerson, Matthew; Gray, Nathanael S.; Hammerman, Peter S. (American Chemical Society, 2015)
      Despite advances in precision medicine approaches over the past decade, the majority of nonsmall cell lung cancers (NSCLCs) are refractory to treatment with targeted small molecule inhibitors. Previous work has identified ...
    • DFG-out Mode of Inhibition by an Irreversible Type-1 Inhibitor Capable of Overcoming Gate-Keeper Mutations in FGF Receptors 

      Huang, Zhifeng; Li, Xiaokun; Tan, Li; Wang, Huiyan; Liu, Yang; Blais, Steven; Deng, Jingjing; Neubert, Thomas A.; Gray, Nathanael S.; Mohammadi, Moosa (American Chemical Society, 2014)
      Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, ...
    • Discovery of 3,5-Diamino-1,2,4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors 

      Deng, Xianming; Wang, Jinhua; Zhang, Jianming; Sim, Taebo; Kim, Nam Doo; Sasaki, Takaaki; Luther, William; George, Rani E.; Jänne, Pasi A.; Gray, Nathanael Schiander (American Chemical Society, 2011)
      A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, ...
    • Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor 

      Kim, Hyung-Gu; Tan, Li; Weisberg, Ellen L.; Liu, Feiyang; Canning, Peter; Choi, Hwan Geun; Ezell, Scott A.; Wu, Hong; Zhao, Zheng; Wang, Jinhua; Mandinova, Anna; Griffin, James D.; Bullock, Alex N.; Liu, Qingsong; Lee, Sam W.; Gray, Nathanael S. (American Chemical Society, 2013)
      The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery ...
    • Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma 

      Wu, Hong; Wang, Wenchao; Liu, Feiyang; Weisberg, Ellen L.; Tian, Bei; Chen, Yongfei; Li, Binhua; Wang, Aoli; Wang, Beilei; Zhao, Zheng; McMillin, Douglas W.; Hu, Chen; Li, Hong; Wang, Jinhua; Liang, Yanke; Buhrlage, Sara J.; Liang, Junting; Liu, Jing; Yang, Guang; Brown, Jennifer R.; Treon, Steven P.; Mitsiades, Constantine S.; Griffin, James D.; Liu, Qingsong; Gray, Nathanael S. (American Chemical Society, 2014)
      BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling ...
    • Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2) 

      Tan, Li; Nomanbhoy, Tyzoon; Gurbani, Deepak; Patricelli, Matthew; Hunter, John; Geng, Jiefei; Herhaus, Lina; Zhang, Jianming; Pauls, Eduardo; Ham, Youngjin; Choi, Hwan Geun; Xie, Ting; Deng, Xianming; Buhrlage, Sara J.; Sim, Taebo; Cohen, Philip; Sapkota, Gopal; Westover, Kenneth D.; Gray, Nathanael S. (American Chemical Society, 2014)
      We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a ...
    • Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery? 

      Zhao, Zheng; Wu, Hong; Wang, Li; Liu, Yi; Knapp, Stefan; Liu, Qingsong; Gray, Nathanael S. (American Chemical Society, 2014)
      The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and ...
    • Golgicide A Reveals Essential Roles for GBF1 in Golgi Assembly and Function 

      Saenz, Jose B.; Sun, William J.; Chang, Jae Won; Li, Jinmei; Bursulaya, Badry; Gray, Nathanael S.; Haslam, David B. (Nature Publishing Group, 2009)
      ADP-ribosylation factor 1 (Arf1) plays a critical role in regulating secretory traffic and membrane transport within the Golgi of eukaryotic cells. Arf1 is activated by guanine nucleotide exchange factors (ArfGEFs) which ...
    • Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells 

      Wu, Hong; Wang, Aoli; Zhang, Wei; Wang, Beilei; Chen, Cheng; Wang, Wenchao; Hu, Chen; Ye, Zi; Zhao, Zheng; Wang, Li; Li, Xixiang; Yu, Kailin; Liu, Juan; Wu, Jiaxin; Yan, Xiao-E; Zhao, Peng; Wang, Jinhua; Wang, Chu; Weisberg, Ellen L.; Gray, Nathanael S.; Yun, Cai-Hong; Liu, Jing; Chen, Liang; Liu, Qingsong (Impact Journals LLC, 2015)
      Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the ...
    • Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase 

      Moccia, Marialuisa; Liu, Qingsong; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Zhao, Zheng; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Billaud, Marc; Gray, Nathanael S.; Carlomagno, Francesca; Santoro, Massimo (Public Library of Science, 2015)
      Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that ...
    • The IkappaB Kinase Family Phosphorylates the Parkinson’s Disease Kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor Signaling 

      Dzamko, Nicolas; Inesta-Vaquera, Francisco; Zhang, Jiazhen; Xie, Chengsong; Cai, Huaibin; Arthur, Simon; Tan, Li; Choi, Hwanguen; Gray, Nathanael Schiander; Cohen, Philip; Pedrioli, Patrick; Clark, Kristopher; Alessi, Dario R. (Public Library of Science, 2012)
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. LRRK2 is highly expressed in immune cells and recent work points towards a link between LRRK2 ...
    • Inhibition of IKKα by BAY61-3606 Reveals IKKα-Dependent Histone H3 Phosphorylation in Human Cytomegalovirus Infected Cells 

      Ho, Catherine M. K.; Donovan-Banfield, I’ah Z.; Tan, Li; Zhang, Tinghu; Gray, Nathanael S.; Strang, Blair L. (Public Library of Science, 2016)
      Protein kinase inhibitors can be used as tools to identify proteins and pathways required for virus replication. Using virus replication assays and western blotting we found that the widely used protein kinase inhibitor ...
    • Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer 

      Dutt, Amit; Ramos, Alex H.; Hammerman, Peter Seth; Mermel, Craig Harold; Cho, Jeonghee; Sharifnia, Tanaz; Chande, Ajit; Tanaka, Kumiko Elisa; Stransky, Nicolas; Greulich, Heidi E.; Gray, Nathanael Schiander; Meyerson, Matthew Langer (Public Library of Science, 2011)
      Background: Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung ...
    • Interleukin-6 Secretion by Astrocytes Is Dynamically Regulated by PI3K-mTOR-Calcium Signaling 

      Codeluppi, Simone; Fernandez-Zafra, Teresa; Sandor, Katalin; Kjell, Jacob; Liu, Qingsong; Abrams, Mathew; Olson, Lars; Gray, Nathanael S.; Svensson, Camilla I.; Uhlén, Per (Public Library of Science, 2014)
      After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the ...
    • The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver 

      Patel, Kashyap; Foretz, Marc; Marion, Allison; Campbell, David G.; Gourlay, Robert; Boudaba, Nadia; Tournier, Emilie; Titchenell, Paul; Peggie, Mark; Deak, Maria; Wan, Min; Kaestner, Klaus H.; Göransson, Olga; Viollet, Benoit; Gray, Nathanael S.; Birnbaum, Morris J.; Sutherland, Calum; Sakamoto, Kei (Nature Pub. Group, 2014)
      LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose ...
    • MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells 

      Wang, Yubao; Lee, Young-Mi; Baitsch, Lukas; Huang, Alan; Xiang, Yi; Tong, Haoxuan; Lako, Ana; Von, Thanh; Choi, Christine; Lim, Elgene; Min, Junxia; Li, Li; Stegmeier, Frank; Schlegel, Robert; Eck, Michael J; Gray, Nathanael S; Mitchison, Timothy J; Zhao, Jean J (eLife Sciences Publications, Ltd, 2014)
      Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we ...
    • Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma 

      Moore, Nathan F.; Azarova, Anna M.; Bhatnagar, Namrata; Ross, Kenneth N.; Drake, Lauren E.; Frumm, Stacey; Liu, Qinsong S.; Christie, Amanda L.; Sanda, Takaomi; Chesler, Louis; Kung, Andrew L.; Gray, Nathanael S.; Stegmaier, Kimberly; George, Rani E. (Impact Journals LLC, 2014)
      Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALKF1174L mutation is sensitive to the ALK inhibitor ...
    • Pharmacological Targeting of the Pseudokinase Her3 

      Xie, Ting; Lim, Sang Min; Westover, Kenneth D.; Dodge, Michael E.; Ercan, Dalia; Ficarro, Scott B.; Udayakumar, Durga; Gurbani, Deepak; Tae, Hyun Seop; Riddle, Steven M.; Sim, Taebo; Marto, Jarrod A.; Jänne, Pasi A.; Crews, Craig M.; Gray, Nathanael S. (2014)
      Her3 (ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be “undruggable” using ATP-competitive small molecules because it lacks ...
    • Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors 

      Ercan, Dalia; Xu, Chunxiao; Yanagita, Masahiko; Monast, Calixte S.; Pratilas, Christine A.; Montero, Joan; Butaney, Mohit; Shimamura, Takeshi; Sholl, Lynette Marie; Ivanova, Elena; Tadi, Madhavi; Rogers, Andrew; Repellin, Claire; Capelletti, Marzia; Maertens, Ophelia; Goetz, Eva Marie; Letai, Anthony George; Garraway, Levi Alexander; Lazzara, Matthew J.; Rosen, Neal; Gray, Nathanael Schiander; Wong, Kwok-Kin; Janne, Pasi Antero (American Association for Cancer Research (AACR), 2012)
      The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by ...