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Human ErbB family of proteins contains four receptor tyrosine kinases (EGFR, Her2, Her3 and Her4) and has been established as a group of attractive druggable targets against diverse cancers. Over the past decades, a variety of ATP-competitive inhibitors have been discovered to target the orthosteric site of EGFR, which, however, would eventually develop acquired drug resistance due to the missense mutations T790M/C797S occurring in orthosteric site. In recent years, a number of forth-generation inhibitors have been successfully designed to overcome the T790M/C797S-induced drug resistance by targeting EGFR allosteric site instead of orthosteric site. Considering that the four proto-oncogenic ErbB kinases share a high conservation in sequence, structure and function, we herein attempted to investigate the binding potency and cross-reactivity of cognate EGFR allosteric inhibitors over noncognate Her2, Her3 and Her4 kinases--they are closely related to gynecological tumors such as ovarian cancer but no allosteric inhibitors have been reported specifically for them to date. A systematic affinity profile of 12 allosteric inhibitors and 4 orthosteric inhibitors to the 4 ErbB kinases was created by integrating dynamics simulations, energetics calculations and biochemical assays, which was then used to derive a systematic inhibitor selectivity profile for EGFR over other three kinases. It is found that allosteric and orthosteric inhibitors exhibit moderate and modest cross-reactivity across the ErbB family, respectively, but the former generally has a higher binding potency than the latter due to the additional energy cost used for inducing kinase conformational change. Moreover, most allosteric inhibitors can be sensitized by Her2 T798M gatekeeper mutation, a counterpart of EGFR T790M gatekeeper mutation that has been previously reported to cause generic drug resistance for orthosteric inhibitors. © 2022. European Biophysical Societies' Association.


Yanli Ma, Bingli Qi, Meiying Ning, Lijuan Zhang, Zeyu An, Jing Zhao. Systematic analysis and molecular profiling of EGFR allosteric inhibitor cross-reactivity across the proto-oncogenic ErbB family kinases by integrating dynamics simulation, energetics calculation and biochemical assay. European biophysics journal : EBJ. 2022 Apr;51(3):283-295

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PMID: 35307752

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