Discovery of EGFR Selective 4,6-Disubstituted Pyrimidines from a Combinatorial Kinase-Directed Heterocycle Library

Zhang, Qiong; Liu, Yi; Gao, Feng; Ding, Qiang; Cho, Charles; Hur, Wooyoung; Jin, Yunho; Uno, Tetsuo; Joazeiro, Claudio A.P.; Gray, Nathanael S.

doi:10.1021/ja0567485

Cited by 49 publications

(42 citation statements)

References 14 publications

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“…Among these most uni-specific kinases are several inhibitors intended to target the epidermal growth factor receptor (EGFR). In fact, the most uni-specific inhibitor, a 4,6-dianilinopyrimidine EGFR inhibitor (CAS# 879127-07-8) with a reported IC 50 of 21 nM for EGFR 22 , inhibited EGFR catalytic activity by >94% but inhibited its next most potent target, MRCKα, by only 22%. In contrast to other EGFR inhibitors tested, this compound also highlights the ability to achieve isoform selective inhibition among the closely related ErbB family kinases 22 .…”

Section: Resultsmentioning

confidence: 99%

“…In fact, the most uni-specific inhibitor, a 4,6-dianilinopyrimidine EGFR inhibitor (CAS# 879127-07-8) with a reported IC 50 of 21 nM for EGFR 22 , inhibited EGFR catalytic activity by >94% but inhibited its next most potent target, MRCKα, by only 22%. In contrast to other EGFR inhibitors tested, this compound also highlights the ability to achieve isoform selective inhibition among the closely related ErbB family kinases 22 . The significant selectivity of this and other uni-specific EGFR inhibitors identified here could reflect unique features of EGFR or, more likely, the unequal attention devoted to the development of inhibitors of this important therapeutic target.…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

et al. 2011

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Small-molecule protein kinase inhibitors are central tools for elucidating cellular signaling pathways and are promising therapeutic agents. Due to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments utilizing these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we profiled the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases using a functional assay. Quantitative analysis revealed complex and often unexpected kinase-inhibitor interactions, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can be used to identify multi-targeted inhibitors of specific, diverse kinases. The results have significant implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments that use them.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

et al. 2011

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“…Importantly, we observed negligible colocalization of the proteins in any other subcellular compartment. To examine whether the ciliary localization of INPP5E was dependent on AURKA activity, we employed a specific AURKA inhibitor, C1368 (Zhang et al, 2006;Plotnikova et al, 2011), but this did not alter INPP5E localization (supplementary material Fig. S1C,D).…”

Section: Introductionmentioning

confidence: 99%

INPP5E interacts with AURKA, linking phosphoinositide signalling to primary cilium stability

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Cottle

et al. 2014

Journal of Cell Science

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Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) cause the ciliopathies known as Joubert and MORM syndromes; however, the role of INPP5E in ciliary biology is not well understood. Here, we describe an interaction between INPP5E and AURKA, a centrosomal kinase that regulates mitosis and ciliary disassembly, and we show that this interaction is important for the stability of primary cilia. Furthermore, AURKA phosphorylates INPP5E and thereby increases its 5-phosphatase activity, which in turn promotes transcriptional downregulation of AURKA, partly through an AKTdependent mechanism. These findings establish the first direct link between AURKA and phosphoinositide signaling and suggest that the function of INPP5E in cilia is at least partly mediated by its interactions with AURKA.

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“…(10) The screen sought compounds that were differentially cytotoxic between murine 32D cells versus 32D cells transformed with Bcr-Abl. Compounds 1 and 4a have a 4,6-disubstituted pyrimidine core structure that has received some attention as an ATP-binding site directed scaffold 11,12 but has not been as extensively investigated as the corresponding 2,4-disubstituted pyrimidines. 13,14 Here, we describe the structure−activity relationships for the 4,6-disubsituted pyrimidine class of Bcr-Abl myristate binding site-targeted ligands.…”

Section: Introductionmentioning

confidence: 99%

Expanding the Diversity of Allosteric Bcr-Abl Inhibitors

et al. 2010

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Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure−activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl−compound 1 cocrystal. We elucidate the structure−activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.

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Discovery of EGFR Selective 4,6-Disubstituted Pyrimidines from a Combinatorial Kinase-Directed Heterocycle Library

Cited by 49 publications

References 14 publications

Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

INPP5E interacts with AURKA, linking phosphoinositide signalling to primary cilium stability

Expanding the Diversity of Allosteric Bcr-Abl Inhibitors

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