Discovery of 3-(1<i>H</i>-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a Potent and Selective Inhibitor of Protein Kinase C Isotypes

Wagner, Jürgen; Matt, Peter; Sedrani, Richard; Albert, Rainer; Cooke, Nigel G.; Ehrhardt, Claus; Geiser, Martin; Rummel, Gabriele; Stark, Wilhelm; Strauss, André; Cowan‐Jacob, Sandra W.; Berthou, Christian; Weckbecker, Gisbert; Evenou, Jean-Pierre; Zenke, Gerhard; Cottens, Sylvain

doi:10.1021/jm901108b

Cited by 107 publications

(80 citation statements)

References 10 publications

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“…This model suggested that cells with tonic BCR signaling may also be sensitive to PKCb inhibition, as this kinase is a critical mediator of CBM complex activation downstream of SYK (9,10). We therefore evaluated the effects of 2 ATP-competitive PKC inhibitors, the pan-PKC inhibitor STN (18,(20)(21)(22) and the PKCa/b-selective compound BHA536 (Novartis; unpublished, see structure and selectivity data in Supplementary Fig. S1) on the proliferation of a panel of DLBCL cell lines.…”

Section: Cd79 Mutant Abc Dlbcl Cell Lines Are Sensitive To Pkc Inhibimentioning

confidence: 99%

“…These results contrast another study that proposed that ligand-independent "tonic" BCR signaling is a more general feature of B-cell lymphomas that renders these cells dependent on downstream BCR signaling (16). To clarify the role of BCR signaling and assess the therapeutic potential of PKC inhibitors in the treatment of DLBCL, we analyzed the response of DLBCL cell lines to treatment with the selective PKC inhibitor sotrastaurin (STN, also known as AEB071), which is currently in phase II clinical trials for psoriasis and solid organ transplantation (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

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Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas

et al. 2011

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The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-kB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-kB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-kB pathway inhibition and were mediated by induction of G 1 -phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities. Cancer Res; 71(7); 2643-53. Ó2011 AACR.

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Section: Cd79 Mutant Abc Dlbcl Cell Lines Are Sensitive To Pkc Inhibimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas

et al. 2011

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“…The overall arrangement of compound 4 adopted a hingebinding conformation, which has been observed for several other ROCK inhibitors and other protein kinase inhibitors ( Fig. 2) (Engh et al, 1996;Mohammadi et al, 1997;Jacobs et al, 2006;Ikuta et al, 2007;Wagner et al, 2009;Tesmer et al, 2010;Lin et al, 2012). The structure revealed that the boron atom is in the trigonal planar conformation as opposed to the tetrahedral configuration.…”

Section: Discussionmentioning

confidence: 53%

“…Comparing the cocrystal structures of ROCK2-compound 4 and the other AGC family kinase members enables the understanding of the selectivity shown in Table 2 (Jacobs et al, 2006;Ikuta et al, 2007;Wagner et al, 2009;Tesmer et al, 2010;Lin et al, 2012). For example, the PKA active site amino acid difference of Ala231 in ROCK2 and Thr183 in PKA may explain the reduced PKA affinity toward the benzoxaborole scaffold.…”

Section: Discussionmentioning

confidence: 99%

Linking Phenotype to Kinase: Identification of a Novel Benzoxaborole Hinge-Binding Motif for Kinase Inhibition and Development of High-Potency Rho Kinase Inhibitors

Akama¹,

Chen²,

Virtucio³

et al. 2013

J Pharmacol Exp Ther

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Benzoxaboroles are a novel class of drug-like compounds that have been rich sources of novel inhibitors for various enzymes and of new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the (aminomethylphenoxy)benzoxaborole family, which potently inhibited Toll-like receptor-stimulated cytokine secretion from leukocytes. After considering their structure-activity relationships and the central role of kinases in leukocyte biology, we performed a kinome-wide screen to investigate the members of the (aminomethylphenoxy)benzoxaborole family. This technique identified Rho-activated kinase (ROCK) as a target. We showed competitive behavior, with respect to ATP, and then determined the ROCK2-drug cocrystal structure. The drug occupies the ATP site in which the oxaborole moiety provides hydrogen bond donors and acceptors to the hinge, and the aminomethyl group interacts with the magnesium/ATP-interacting aspartic acid common to protein kinases. The series exhibits excellent selectivity against most of the kinome, with greater than 15-fold selectivity against the next best member of the AGC protein kinase subfamily. Medicinal chemistry efforts with structure-based design resulted in a compound with a K i of 170 nM. Cellular studies revealed strong enzyme inhibition rank correlation with suppression of intracellular phosphorylation of a ROCK substrate. The biochemical potencies of these compounds also translated to functional activity, causing smooth muscle relaxation in rat aorta and guinea pig trachea. The series exhibited oral availability and one member reduced rat blood pressure, consistent with ROCK's role in smooth muscle contraction. Thus, the benzoxaborole moiety represents a novel hinge-binding kinase scaffold that may have potential for therapeutic use.

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“…The natural product, staurosporine, although a potent inhibitor of PKC, has limited selectivity in vitro for both ATP-dependent kinases and individual PKC isozymes (Tamaoki et al, 1986). A series of novel indolylmaleimides were developed for clinical trials (Zhao et al, 2008), such as Enzastaurin (Chen and LaCasce, 2008) and Sotrastaurin (Wagner et al, 2009). Enzastaurin is an acyclic bisindolylmaleimide derivative that potently and selectively inhibits PKC isoforms.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxicity of novel 3-amino-4-indolylmaleimide derivatives

et al. 2011

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In an attempt to develop potent and selective antitumor agents, a series of novel 3-amino-4-indolylmaleimides were designed and synthesized. The reaction showed high regioselectivity. The structure of compound 7a was determined by an X-ray single crystal diffraction method. The cytotoxicities of the title compounds were evaluated against HeLa, SMMC 7721 and HL 60 cancer cell lines by a standard MTT assay in vitro. The pharmacological results showed that some of the title compounds displayed moderate or high cytotoxic activity against the tested cell lines. Compound 7d was the most promising compound against the tested cancer cell lines. Structure-activity relationships are discussed based on the experimental data obtained. A hydroxyethylamino group at the 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity.

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Discovery of 3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a Potent and Selective Inhibitor of Protein Kinase C Isotypes

Cited by 107 publications

References 10 publications

Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas

Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas

Linking Phenotype to Kinase: Identification of a Novel Benzoxaborole Hinge-Binding Motif for Kinase Inhibition and Development of High-Potency Rho Kinase Inhibitors

Synthesis and cytotoxicity of novel 3-amino-4-indolylmaleimide derivatives

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