Optimization of 2-Phenylaminoimidazo[4,5-<i>h</i>]isoquinolin-9-ones:  Orally Active Inhibitors of lck Kinase

Goldberg, Daniel R.; Butz, Tanja; Cardozo, Mario; Eckner, Robert J.; Hammach, Abdelhakim; Huang, Jessica; Jakes, Scott; Kapadia, Suresh; Kashem, Mohammed A.; Lukas, Susan; Morwick, Tina M.; Panzenbeck, M. J.; Patel, Usha; Pav, Susan; Peet, Gregory W.; Peterson, Jeffrey D.; Prokopowicz, Anthony S.; Snow, Roger J.; Sellati, Rosemarie; Takahashi, Hidenori; Tan, Jonathan; Tschantz, Matt A.; Wang, Xiaojun; Wang, Yong; Wolak, John P.; Xiong, Pla; Moss, Neil

doi:10.1021/jm020446l

Cited by 45 publications

(21 citation statements)

References 21 publications

(68 reference statements)

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“…Noteworthy, treatment with a selective Lck inhibitor 76 led to a significantly greater decrease in mean intensity levels of phospho‐Cas‐L than treatment with the selective ZAP70 inhibitor piceatannol, 74 suggesting that Cas‐L phosphorylation depends on Lck activity (Figures 2d and e).…”

Section: Resultsmentioning

confidence: 99%

“…The Src‐family kinase inhibitor PP2 73 was added to 1 × 10 6 cells in 100 μl at a final concentration of 10 μ m , incubated for 15 min at 37 °C, and added to the bilayers. Treatments with Lck inhibitor (10 μ m 76 ), Lck and Syk‐family inhibitor Piceatannol (10 μ m 74 ), PKCθ inhibitor C20 (10 μ m or 33 μ m 72 ), Arp2/3 inhibitor CK666 (10 μ m ), and actin polymerization inhibitor cytochalasin D (60 n m or 200 n m ) followed similar protocol described for PP2. All inhibitors were dissolved in DMSO, and all pharmacological experiments performed included a DMSO only incubation control.…”

Section: Methodsmentioning

confidence: 99%

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Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

et al. 2016

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The immunological synapse formed between a T cell and an antigen presenting cell is important for cell-cell communication during T cell mediated immune responses. Immunological synapse formation begins with stimulation of the T cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization-dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte-specific Crk-associated substrate (Cas-L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas-L is phosphorylated at TCR microclusters in an actin polymerization-dependent fashion. Furthermore, Cas-L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside-out integrin activation, and actomyosin contraction. We propose a new role for Cas-L in T cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T cell mediated immune responses.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

et al. 2016

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“…Thus, small molecule inhibitors are attractive because they usually function within seconds and often do not require any other cell manipulation. Selective inhibitors of several TCR proximal cytoplasmic kinases such as Lck have been reported ( 15 ). Yet, despite much interest, no selective cell-permeable ZAP-70 inhibitors, other than a peptide inhibitor, have been reported, suggesting that this kinase presents a significant challenge to inhibitor development ( 16 ).…”

mentioning

confidence: 99%

Inhibition of ZAP-70 Kinase Activity via an Analog-sensitive Allele Blocks T Cell Receptor and CD28 Superagonist Signaling

Levin

Zhang

Kadlecek

et al. 2008

Journal of Biological Chemistry

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ZAP-70 is a cytoplasmic protein tyrosine kinase that is required for T cell antigen receptor (TCR) signaling. Both mice and humans deficient in ZAP-70 fail to develop functional T cells, thus demonstrating its necessity for T cell development and function. There is currently no highly specific, cell-permeable, small molecule inhibitor for ZAP-70; therefore, we generated a mutant ZAP-70 allele that retains kinase activity but is sensitive to inhibition by a mutant-specific inhibitor. We validated the chemical genetic inhibitor system in Jurkat T cell lines, where the inhibitor blocked ZAP-70-dependent TCR signaling in cells expressing the analog-sensitive allele. Interestingly, the inhibitor also ablated CD28 superagonist signaling, thereby demonstrating the utility of this system in dissecting the requirement for ZAP-70 in alternative mechanisms of T cell activation. Thus, we have developed the first specific chemical means of inhibiting ZAP-70 in cells, which serves as a valuable tool for studying the function of ZAP-70 in T cells.

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“…To perform pharmacophore modeling calculations a dataset of 85 known inhibitors of Btk with diverse scaffold collected from different literature resources [ 26 – 29 ] and classified into two different data sets: (i) a training set and (ii) a test set. Training set was used to generate the hypothesis while the generated hypothesis was validated by a test set.…”

Section: Methodsmentioning

confidence: 99%

Exploration of Novel Inhibitors for Bruton’s Tyrosine Kinase by 3D QSAR Modeling and Molecular Dynamics Simulation

et al. 2016

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Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in many cellular signaling pathways. B cell malignancies are dependent on BCR signaling, thus making BTK an efficient therapeutic target. Over the last few years, significant efforts have been made in order to develop BTK inhibitors to treat B-cell malignancies, and autoimmunity or allergy/hypersensitivity but limited success has been achieved. Here in this study, 3D QSAR pharmacophore models were generated for Btk based on known IC50 values and experimental energy scores with extensive validations. The five features pharmacophore model, Hypo1, includes one hydrogen bond acceptor lipid, one hydrogen bond donor, and three hydrophobic features, which has the highest correlation coefficient (0.98), cost difference (112.87), and low RMS (1.68). It was further validated by the Fisher’s randomization method and test set. The well validated Hypo1 was used as a 3D query to search novel Btk inhibitors with different chemical scaffold using high throughput virtual screening technique. The screened compounds were further sorted by applying ADMET properties, Lipinski’s rule of five and molecular docking studies to refine the retrieved hits. Furthermore, molecular dynamic simulation was employed to study the stability of docked conformation and to investigate the binding interactions in detail. Several important hydrogen bonds with Btk were revealed, which includes the gatekeeper residues Glu475 and Met 477 at the hinge region. Overall, this study suggests that the proposed hits may be more effective inhibitors for cancer and autoimmune therapy.

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Optimization of 2-Phenylaminoimidazo[4,5-h]isoquinolin-9-ones: Orally Active Inhibitors of lck Kinase

Cited by 45 publications

References 21 publications

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

Inhibition of ZAP-70 Kinase Activity via an Analog-sensitive Allele Blocks T Cell Receptor and CD28 Superagonist Signaling

Exploration of Novel Inhibitors for Bruton’s Tyrosine Kinase by 3D QSAR Modeling and Molecular Dynamics Simulation

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