Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases

Dandu, Reddeppareddy; Zulli, Allison L.; Bacon, Edward R.; Underiner, Ted L.; Robinson, Charles Alexander; Chang, Hong; Miknyoczki, Sheila; Grobelny, Jennifer V.; Ruggeri, Bruce; Yang, Shi; Albom, Mark S.; Angeles, Thelma S.; Aimone, Lisa D.; Hudkins, Robert L.

doi:10.1016/j.bmcl.2008.02.001

Cited by 15 publications

(9 citation statements)

References 24 publications

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“…A total of 263 compounds were obtained [13][14][15][16][17][18][19][20][21]. From these compounds a quantitative pharmacophore model was developed with the aid of HypoRefine module within Catalyst [22].…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

Xie

Ren

et al. 2009

Journal of Molecular Graphics and Modelling

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Section: Introductionmentioning

confidence: 99%

Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

Xie

Ren

et al. 2009

Journal of Molecular Graphics and Modelling

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“…These sometimes target kinases in the same kinome sub-family [42] but can also be directed against two functionally related kinases from different kinome sub-families, as in the example of dual inhibitors of Chk1 and Wee1 which are both involved in the G2 cell cycle checkpoint [130]. Studies by several groups have shown that dual inhibitors of the protein kinase mTOR and the lipid kinase phosphoinositide 3-kinase (PI3K) may have better efficacy in certain cancer types compared to more specific inhibitors [5,20,32,51,67,110,118].…”

Section: The Importance Of Determining Selectivitymentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.

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“…Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar dual TIE-2 and VEGFR-2 receptor tyrosine kinase inhibitors, with the most potent being compound 27 . This compound inhibited VEGF-induced human umbilical vein endothelial cell (HUVEC) capillary-tube formation and was orally active in an A375 human tumor xenograft melanoma model with no observed toxicity [ 70 ].…”

Section: Miscellaneous Oxime Group-containing Kinase Inhibitorsmentioning

confidence: 99%

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

et al. 2021

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Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.

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Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases

Cited by 15 publications

References 24 publications

Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

Measuring and interpreting the selectivity of protein kinase inhibitors

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

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