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Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

ABSTRACT: Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. In most cases, this resistance is in the form of the T790M mutation. Here, we report the design, synthesis and biochemical evaluation of a novel series of irreversible EGFR tyrosine kinase inhibitors (EGFR-TKIs) that are derived from the anilinoquinazoline scaffold. Guided by molecular modeling, this series of analogs was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and to achieve high levels of anti-tumor activity in cell cultures and in xenografts. The most promising compound 13c ((E) -N - (4 - (4 - (3-fluorobenzyloxy) -3- chlorophenylamino) -7-ethoxyquinazolin-6-yl) -3- ((S) -pyrrolidin-2-yl)acrylamide, which we named Transtinib) displayed strong anti-proliferative activity against the H1975 and A431 cell lines with IC50 values of 34 nM and 62 nM, respectively. In xenograft models, Transtinib significantly decreases tumor size for a prolonged period of time. These results suggest that Transtinib is a potential cancer therapeutic drug lead for the inhibition of mutant EGFR to overcome the development of resistance.

SUBMITTER: Hu P

PROVIDER: S-EPMC5094958 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

Hu Peng P Han Da-Xiong DX Ruan Run-Sheng RS Zheng Li-Mou LM Chou Shiu-Huey SH Tzeng Chi-Meng CM

Oncotarget 20160601 24

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. In most cases, this resistance is in the form of the T790M mutation. Here, we report the design, synthesis and biochemical evaluation of a novel series of irreversible EGFR tyrosine kinase inhibitors (EGFR-TKIs) that are der ...[more]

PMID: 26848869

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Project description:Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC50 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

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Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

Publications

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

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