Chemoproteomics‐Aided Medicinal Chemistry for the Discovery of EPHA2 Inhibitors

Heinzlmeir, Stephanie; Lohse, Jonas; Treiber, Tobias; Kudlinzki, D.; Linhard, V.L.; Gande, S.L.; Sreeramulu, Sridhar; Saxena, Krishna; Liu, Xiaofeng; Wilhelm, Mathias; Schwalbe, Harald; Küster, Bernhard; Médard, Guillaume

doi:10.1002/cmdc.201700217

Cited by 25 publications

(21 citation statements)

References 52 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dasatinib has also been recently used as a lead structure for developing EPHA2-inhibitors with ameliorated targeting profiles. The novel EphA2 inhibitor candidate 4a based on dasatinib was shown to feature an ameliorated selectivity profile while maintaining potent inhibitory effects against EphA2 as well as cytotoxic properties in glioblastoma cells [69].…”

Section: Inhibiting Kinase Activity Of Epha2mentioning

confidence: 99%

Targeting EphA2 in cancer

et al. 2020

View full text Add to dashboard Cite

Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success. The present review briefly describes the contribution of EphA2-ephrin A1 signaling axis to carcinogenesis. In addition, the roles of EphA2 in resistance to molecular-targeted agents were examined. In particular, we focused on EphA2's potential as a target for cancer treatment to provide insights into the application of EphA2 targeting in anticancer strategies. Overall, EphA2 represents a potential target for treating malignant tumors.

show abstract

Section: Inhibiting Kinase Activity Of Epha2mentioning

confidence: 99%

Targeting EphA2 in cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Nevertheless, several attempts aimed at improving their specificity. Chemical modifications of Dasatinib have reduced the number of its known targets from 44 to 31 while keeping its high affinity for EphA2 [142]. Similarly, a few optimized KIs with enhanced specificity for EphA3 have been developed, however still with cross-reactivity with many other kinases [143].…”

Section: Small Moleculesmentioning

confidence: 99%

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

2020

View full text Add to dashboard Cite

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

show abstract

“…In addition, EPHA2 knock‐down or ephrin‐A1 treatment of resistant cells decreased FAK phosphorylation and cell migration . In another study, Heinzlmeir et al . aimed at development of EPHA2 inhibitors with improved target profile, with dasatinib used as a basis of a lead structure.…”

Section: Chemical Proteomics For Drug Selectivity and Inhibitor Bindingmentioning

confidence: 99%

Proteomics in Drug Development: The Dawn of a New Era?

Frantzi

Latosinska

Mischak

2019

Proteomics Clinical Apps

View full text Add to dashboard Cite

Mass spectrometry offers the potential of acquiring high resolution data depicting the functional status of a group of healthy or diseased individuals, according to different conditions. As most of the drugs are currently targeting proteins, proteomics has a dual value, both in the discovery of new molecules as therapeutic targets, but also as a methodology to perform high throughput drug profiling. As there is an evident need for drugs to be improved in terms of efficacy, a mechanistic insight for downstream effectors can be valuable in order to predict side effects and resistance mechanisms. Recently developed assays, like thermal proteome profiling enables comprehensive drug target profiling and is, therefore, of high value in drug discovery. In this review, a systematic literature search is conducted and the most prominent proteomics studies as implicated in assisting drug discovery and development is presented. Focus is placed on investigations that are closer to implementation, therefore particular emphasis is given in studies conducted in human diseased population and further verified in vitro or in vivo.

show abstract

Chemoproteomics‐Aided Medicinal Chemistry for the Discovery of EPHA2 Inhibitors

Cited by 25 publications

References 52 publications

Targeting EphA2 in cancer

Targeting EphA2 in cancer

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

Proteomics in Drug Development: The Dawn of a New Era?

Contact Info

Product

Resources

About