Mutant EGFR inhibitor

Mutant EGFR inhibitor is a selective and potent Mutated EGFR inhibitor(L858R activating mutant, the Exonl9 deletion activating mutant and the T790M resistance mutant).

Sequential treatment of tyrosine kinase inhibitor and platinum-based doublet chemotherapy on EGFR mutant non-small cell lung cancer: a meta-analysis of randomized controlled clinical trials.[Pubmed:28280362]

Onco Targets Ther. 2017 Feb 28;10:1279-1284.

There is debate surrounding which treatment is superior in overall survival (OS) rates in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC); first-line tyrosine kinase inhibitor (TKI) followed by second-line platinum-based doublet chemotherapy (PCT), or the reverse sequence. Cross treatment of first- and second-line TKI and PCT makes it difficult to deduce which sequence (TKI-PCT or PCT-TKI) is better for OS. Using the keywords "lung cancer" and "EGFR" we identified clinical trials within the PubMed database which were published between January 2006 and November 2016. Basic characteristics and OS with hazard ratio and 95% confidence intervals were searched and analyzed. In total, 457 articles were reviewed and nine clinical trials with 1,876 patients were of sufficient quality for further analysis. Fixed effects models were performed to pool the data in this meta-analysis. All nine studies were open-labeled, multicenter, Phase III randomized controlled clinical trials. The pooled hazard ratio was 0.96 (95% confidence interval: 0.84-1.10) for OS between first-line TKI followed by second-line PCT compared to the reverse sequence. No statistically significant heterogeneity (I(2)=0, P=0.553) nor publication bias (Egger's P=0.991) was observed among these studies. In conclusion, there was no OS benefit between first-line TKI followed by second-line PCT compared to the reverse sequence in EGFR mutant NSCLC patients. Chemotherapy was still useful and irreplaceable for the treatment of NSCLC, especially for those patients with EGFR unavailable for testing.

Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells.[Pubmed:27649127]

Molecules. 2016 Sep 15;21(9). pii: molecules21091236.

In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [(3)H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 microM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers.

Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]py rimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.[Pubmed:28282122]

J Med Chem. 2017 Apr 13;60(7):2944-2962.

On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases.[Pubmed:27928026]

Sci Transl Med. 2016 Dec 7;8(368):368ra172.

Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate. We report the discovery and early clinical development of AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice. An early clinical study in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant properties and antitumor activities. Our data demonstrate the potential of AZD3759 for the treatment of BM and LM and support its further clinical evaluation in larger trials.

Mutant EGFR inhibitor is a selective and potent Mutated EGFR inhibitor(L858R activating mutant, the Exonl9 deletion activating mutant and the T790M resistance mutant).

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