2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: Design and synthesis of a potent and isoform selective PKC-ζ inhibitor

Trujillo, John I.; Kiefer, James R.; Huang, Wei; Thorarensen, Atli; Li, Xing; Caspers, Nicole; Day, Jacqueline E.; Mathis, Karl J.; Kretzmer, Kuniko K.; Reitz, Beverley; Weinberg, Robin A.; Stegeman, Roderick A.; Wrightstone, Ann D.; Christine, Lori J.; Compton, Robert P.; Xiong, Lixia

doi:10.1016/j.bmcl.2008.11.105

Cited by 56 publications

(52 citation statements)

References 22 publications

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“…1C, blue trace); in contrast 5 M PZ09 had no effect on PKC␣ activity in cells (Fig. 1C, red trace), confirming previous selectivity results performed in vitro (41). Thus, monitoring PZ09-sensitive phosphorylation of CKAR is an effective tool to measure aPKC activity in cells.…”

Section: Pz09 Inhibits Atypical Pkcs But Not Conventional Pkcs Insupporting

confidence: 75%

“…in Cells-Although in vitro inhibition studies of PZ09 have demonstrated its selectivity for aPKC over other PKCs (41), PZ09 also inhibited several other non-PKC kinases, including PDK1, PKA, and p70 S6K when used at 10 M concentration. To examine the effects of increasing PZ09 concentrations on endogenous readouts of aPKC, PDK1, and cPKC, we pre-treated cells with PZ09 followed by stimulation with insulin prior to lysis to achieve optimal readout of PDK1 activity on the agonist-induced site p308 Akt (lane 2 versus lane 1, Fig.…”

Section: Higher Concentrations Of Pz09 Have Off-target Effects On Endmentioning

confidence: 99%

“…aPKC in vitro (41) and already used for studies in vivo (42) for selective modulation of aPKC substrate readouts in cells. Using a genetically encoded FRET reporter, the C kinase activity reporter (CKAR) (34) previously validated for measurement of aPKC activity in real time in live cells (5, 6, 40), we examined inhibition of endogenous aPKC or mCherry-tagged constructs of aPKC by PZ09.…”

Section: Pz09 Inhibits Atypical Pkcs But Not Conventional Pkcs Inmentioning

confidence: 99%

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Protein Scaffolds Control Localized Protein Kinase Cζ Activity

Tobias

Newton²

2016

Journal of Biological Chemistry

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Atypical protein kinase C (aPKC) isozymes modulate insulin signaling and cell polarity, but how their activity is controlled in cells is not well understood. These enzymes are constitutively phosphorylated, insensitive to second messengers, and have relatively low activity. Here we show that protein scaffolds not only localize but also differentially control the catalytic activity of the aPKC PKC, thus promoting activity toward localized substrates and restricting activity toward global substrates. Using cellular substrate readouts and scaffolded activity reporters in live cell imaging, we show that PKC has highly localized and differentially controlled activity on the scaffolds p62 and Par6. Both scaffolds tether aPKC in an active conformation as assessed through pharmacological inhibition of basal activity, monitored using a genetically encoded reporter for PKC activity. However, binding to Par6 is of higher affinity and is more effective in locking PKC in an active conformation. FRETbased translocation assays reveal that insulin promotes the association of both p62 and aPKC with the insulin-regulated scaffold IRS-1. Using the aPKC substrate MARK2 as another readout for activity, we show that overexpression of IRS-1 reduces the phosphorylation of MARK2 and enhances its plasma membrane localization, indicating sequestration of aPKC by IRS-1 away from MARK2. These results are consistent with scaffolds serving as allosteric activators of aPKCs, tethering them in an active conformation near specific substrates. Thus, signaling of these intrinsically low activity kinases is kept at a minimum in the absence of scaffolding interactions, which position the enzymes for stoichiometric phosphorylation of substrates co-localized on the same protein scaffold.

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Section: Pz09 Inhibits Atypical Pkcs But Not Conventional Pkcs Insupporting

confidence: 75%

Section: Higher Concentrations Of Pz09 Have Off-target Effects On Endmentioning

confidence: 99%

Section: Pz09 Inhibits Atypical Pkcs But Not Conventional Pkcs Inmentioning

confidence: 99%

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Protein Scaffolds Control Localized Protein Kinase Cζ Activity

Tobias

Newton²

2016

Journal of Biological Chemistry

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“…Imidazoles are one of the interesting heterocycles which employed widely in medicine chemistry and their unique biological activities such as antiinflammatory [5], anti-parasitic [6], antifungal [7], antiviral [8].…”

Section: Introductionmentioning

confidence: 99%

<strong>Magnetic halloysite: an envirmental nanocatalyst for the synthesis of benzoimidazoles</strong>

Maleki

Hajizadeh

2017

Proceedings of the 21st International Electronic Conference on Synthetic Organic Chemistry

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In the present work, halloysite nanotubes was modified by magnetic nanoparticles and used as an efficient, eco-friendly catalyst in synthesize of benzoimidazole derivatives. This synthesized nanocomposite was characterized successfully by Fourier transforms infrared spectroscopy (FT-IR), scanning electron microscopy (SEM). The catalyst can simply be separated from the reaction mixture by an external magnet and reused in several runs. Reusable and easily recoverable catalyst, use of green solvent, room temperature and mild reaction conditions are some advantages of the present work.

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“…These types of compounds are known to display a broad range of pharmaceutical and industrial applications. Imidazole cores are present in many compounds with pronounced biologic activities such as angiotensin inhibitors [3], anti-inflammatory [4], glucagon antagonist [5], antiviral [6], antimicrobial [7], fungicidal [8], and high cytotoxicity, which have indicated them as new candidates in cancer therapy [9]. In recent years, alkylated imidazoliums are substantially used in ionic liquids [10] that have been given a new approach to environmentally-benign and green chemistry.…”

Section: Introductionmentioning

confidence: 99%