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Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode

View Article: PubMed Central - PubMed

ABSTRACT

EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct “DFG-in” and “cHelix-out” inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.

No MeSH data available.


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Effect of CHMFL-EGFR-26 on cell cycle progression and apoptosis in EGFR mutants/wt NSCLC cell lines
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Figure 3: Effect of CHMFL-EGFR-26 on cell cycle progression and apoptosis in EGFR mutants/wt NSCLC cell lines

Mentions: We then examined CHMFL-EGFR-26's effect on cell cycle progression and apoptosis. Not surprisingly, in the drug sensitive cell lines including H1975, HCC827, PC9 and H3255 which expressed EGFR mutants, CHMFL-EGFR-26 dramatically blocked cell cycle at G0/G1 phase in a dose-dependent manner at 24-hour. While for NSCLC cell lines with wild-type EGFR (A549 and H1355), CHMFL-EGFR-26 did not cause cell cycle arrest at concentrations up to 3 μM after 72-hour treatment. (Figure 3A) CHMFL-EGFR-26 also induced apoptosis in EGFR mutant NSCLC cell lines in a dose-dependent manner (Figure 3B). In H1975, HCC827, PC9 and H3255, 30nM concentration of CHMFL-EGFR-26 was sufficient to induce Caspase-3 and PARP cleavage after 24hrs of treatment. However, in EGFR wt NSCLC cell lines, even after 72hrs drug treatment, there was no cleaved Caspase-3 and PARP detected. This result was correlated with the growth inhibition effects observed in different NSCLC cell lines.


Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode
Effect of CHMFL-EGFR-26 on cell cycle progression and apoptosis in EGFR mutants/wt NSCLC cell lines
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392334&req=5

Figure 3: Effect of CHMFL-EGFR-26 on cell cycle progression and apoptosis in EGFR mutants/wt NSCLC cell lines
Mentions: We then examined CHMFL-EGFR-26's effect on cell cycle progression and apoptosis. Not surprisingly, in the drug sensitive cell lines including H1975, HCC827, PC9 and H3255 which expressed EGFR mutants, CHMFL-EGFR-26 dramatically blocked cell cycle at G0/G1 phase in a dose-dependent manner at 24-hour. While for NSCLC cell lines with wild-type EGFR (A549 and H1355), CHMFL-EGFR-26 did not cause cell cycle arrest at concentrations up to 3 μM after 72-hour treatment. (Figure 3A) CHMFL-EGFR-26 also induced apoptosis in EGFR mutant NSCLC cell lines in a dose-dependent manner (Figure 3B). In H1975, HCC827, PC9 and H3255, 30nM concentration of CHMFL-EGFR-26 was sufficient to induce Caspase-3 and PARP cleavage after 24hrs of treatment. However, in EGFR wt NSCLC cell lines, even after 72hrs drug treatment, there was no cleaved Caspase-3 and PARP detected. This result was correlated with the growth inhibition effects observed in different NSCLC cell lines.

View Article: PubMed Central - PubMed

ABSTRACT

EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct “DFG-in” and “cHelix-out” inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.

No MeSH data available.


Related in: MedlinePlus