Revisiting the molecular mechanism of acquired resistance to reversible tyrosine kinase inhibitors caused by EGFR gatekeeper T790M mutation in non-small-cell lung cancer

Zhao, Yan; Jiao, Yingjie; Sun, Fengzhe; Li, Xudong

doi:10.1007/s00044-018-2224-7

Cited by 14 publications

(4 citation statements)

References 54 publications

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“…Traditionally, it is thought that the NSCLC EGFR missense mutations can confer drug resistance by creating unfavorable interactions such as steric hindrance and electrostatic repulsion with inhibitor molecules. [17,18] However, Yun and coworkers have performed fluorescence quenching assays to study the intermolecular interactions of ATP with wild-type and mutant EGFR; they found that the T790M-induced drug resistance is caused by improving the kinase affinity for ATP rather than by sterically blocking the binding of TKIs, and thus the T790M can be regarded as a "generic" resistance mutation that will reduce the potency of any ATPcompetitive reversible kinase inhibitor. [19] Further study revealed that a number of EGFR missense mutations can considerably or moderately reshape the binding behavior of ATP to EGFR ATP site, thus indirectly influencing the inhibitory capability of ATP-completive inhibitors against EGFR kinase.…”

Section: Thermodynamic Effects Of Allosteric Inhibitors and Egfr Muta...mentioning

confidence: 99%

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Zhao

Zhu

Gao

2021

J Chinese Chemical Soc

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Human epidermal growth factor receptor (EGFR) is an attractive anti-non-small cell lung cancer (anti-NSCLC) druggable target, but many traditional adenosine triphosphate (ATP)-competitive EGFR inhibitors have been clinically observed to eventually establish acquired resistance due to kinase mutations. Allosteric inhibitors represent a new direction of EGFR-targeted therapy, which have been successfully developed since 2016 to overcome the widely occurring kinase drug-resistant mutations T790M/C797S [Jia Y, et al. Nature 2016; 534: 129-132].In this study, a systematic inhibitor response-to-mutation profile of 11 reported EGFR allosteric inhibitors against 17 clinically significant EGFR missense muta-

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Section: Thermodynamic Effects Of Allosteric Inhibitors and Egfr Muta...mentioning

confidence: 99%

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Zhao

Zhu

Gao

2021

J Chinese Chemical Soc

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“…The quantum mechanics/molecular mechanics (QM/MM) 38 was employed to refine the intermolecular interaction between the protein and ligand of PARP1/2‐inhibitor complex system. The system was partitioned into two layers 39 : the inhibitor ligand and the nonidentical enzyme active‐site residues (NEARs) were included in inner layer and treated with a high‐level semiempiricial theory of AM1, while rest of the system was in outer layer and described using a low‐level force field of UFF. The NEARs represent active site variability over the two enzymes and are thought to be primarily responsible for inhibitor selectivity.…”

Section: Methodsmentioning

confidence: 99%

Systematic inhibitor selectivity between PARP1 and PARP2 enzymes: Molecular implications for ovarian cancer personalized therapy

Zuo

Zhao

2021

J of Molecular Recognition

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Human poly(ADP‐ribose) polymerases (PARPs) are a class of nuclear enzymes involved in the pathogenesis of diverse gynecologic tumors. The PARP1 and PARP2 are the two most documented members in PARP family, which have been approved as the druggable targets of ovarian and cervical cancers. Selective targeting of the two enzymes with small‐molecule inhibitors is a great challenge due to the high conservation in catalytic domain and active site. Here, we investigate the systematic selectivity profile of sophisticated PARP inhibitors between the two enzymes. Computational methods are used to model/optimize the complex structures of inhibitor ligands with PARP1/2 catalytic domains and then to estimate the theoretical Fenzymatic assays exhibit a good consistence with theoretical selectivity over six tested inhibitor samples (rc2 = 0.857). It is revealed that the inhibitor selectivity is conferred from the exquisite difference in the residue composition and structural architecture of both the local activity sites and the whole catalytic domains of the two enzymes. In particular, the TMZ50 and ME0328 show strong selectivity between PARP1 and PARP2, but only the former has a potent activity on the two enzymes, whereas the latter can only inhibit the enzymes moderately. These compounds can be considered as potential lead molecular entities to develop new specific PARP‐selective inhibitor drugs for personalized therapy combating gynecologic cancers.

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“…The interaction energy between SSBI and mutant residue was analyzed at a high level of ab initio electron‐correlation theory. [ 45 ] The residue–SSBI interaction was stripped from the refined kinase–SSBI complex system, and MP2/aug‐cc‐pVDZ single‐point energy calculations were then performed separately for residue–SSBI complex ( E c ), residue monomer ( E r ), and SSBI monomer ( E s ). Therefore, the interaction energy can be derived as Δ E = E c − E r − E s , where the basis set superposition error was corrected by counterpoise method.…”

Section: Methodsmentioning

confidence: 99%

Systematic response of staurosporine scaffold‐based inhibitors to drug‐resistant cancer kinase mutations

2020

Archiv der Pharmazie

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Human protein kinases have been established as promising druggable targets in cancer therapy. However, a large number of acquired drug-resistant kinase mutations are observed after first-and second-line kinase inhibitor treatments, largely limiting the application of small-molecule inhibitors in the targeted cancer therapy.Previously, the pan-kinase inhibitor staurosporine and its derivatives have been reported to selectively inhibit gatekeeper mutants over wild-type kinases, suggesting that the staurosporine scaffold is potentially helpful in developing wild-typesparing inhibitors of drug-resistant kinase mutants. Here, a systematic response profile of 32 staurosporine scaffold-based inhibitors (SSBIs) for 61 ontologyenriched drug-resistant cancer kinase mutations is created using a combination of in silico analysis and in vitro assay, from which it is possible to identify those mutations that have the potential to cause resistance or confer sensitivity to SSBIs. The profile reveals that SSBIs exhibit distinct responses to kinase gatekeeper and nongatekeeper mutations, and SSBIs bearing p7 substituents can considerably influence their response to kinase gatekeeper mutations, particularly for the mutations of the Ile residue, which possesses a Cβ methyl group that tends to cause steric clash with bound SSBIs. Nongatekeeper mutations generally have a moderate and unfavorable effect on SSBI activity, as most of them are outside the kinase active site and do not directly contact inhibitor ligands. In addition, it is found that resistance is commonly caused by mutation-induced hindrance effects, whereas sensitivity is primarily conferred by mutation-established additional interactions. K E Y W O R D Sdrug-resistant kinase mutation, inhibitor selectivity, protein kinase, staurosporine scaffold-based inhibitor, targeted cancer therapy

show abstract

Revisiting the molecular mechanism of acquired resistance to reversible tyrosine kinase inhibitors caused by EGFR gatekeeper T790M mutation in non-small-cell lung cancer

Cited by 14 publications

References 54 publications

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Systematic inhibitor selectivity between PARP1 and PARP2 enzymes: Molecular implications for ovarian cancer personalized therapy

Systematic response of staurosporine scaffold‐based inhibitors to drug‐resistant cancer kinase mutations

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