Abstract LB-271: Antitumor activity of new epidermal growth factor receptor inhibitors in non-small cell lung and breast cancer
Authors: DOUKATAS ARIS , Gavriil Efthymios-Spyridon , Karampelas Theodoros , Marakos Panagiotis , Pouli Nicole , Tamvakopoulos Constantin 
Published: August 2018

Non-small cell lung cancer (NSCLC) and breast cancer (BrCa) are two of the most common forms of cancer. Since EGFR and HER2 are proven to be key targets in cancer therapy, we have designed and synthesized new molecules, belonging to a distinct chemical category of the existing drugs. Lapatinib was selected as an ideal prototype compound for the design of new analogues with potential action against EGFR and HER2 due to its ability to target and inhibit both receptors with great selectivity and efficiency.

Structural analogues of lapatinib were synthesized by replacing the central ring of quinazoline by purine or bioisosteric rings aiming to investigate and potentially ameliorate the biological and pharmacological action. For the preparation of the target molecules, synthetic pathways have been designed and developed, which allow their high yielding preparation. The potency of the various analogues was evaluated in vitro using the following methodologies: MTT cytotoxic assay, Western Blot and ELISA assays to evaluate the ability of the analogues to inhibit EGFR phosphorylation in comparison with the activity of lapatinib and cell uptake studies based on mass spectrometry techniques.

From a pool of 12 different analogues, two compounds, an imidazopyridine and an imidazopyrimidine derivative had the highest potencies, which were comparable to lapatinib in the NSCLC cell line A549 and in the BrCa cell line HCC-1954 (using MTT cytotoxic assays average IC50 values of 3 μM & 30 μM, respectively versus 11 μM for lapatinib). The same compounds were also tested in the NSCLC cell line NCI-H1975, which harbours the L858R + T790M mutations responsible for resistance (average IC50 values of 10 μM & 30 μM, respectively versus 9 μM for lapatinib). In addition, by using Western Blot and ELISA assays the two agents were the most potent compared to lapatinib, as they caused 50% inhibition of pEGFR at a 10 μM concentration. We have shown that the imidazopyridine derivative enters the A549 cells at a relatively slower rate in comparison to lapatinib. Presumably the physicochemical properties of the analogue are responsible for its higher accumulation (at 48 h incubation intracellular concentration of 17 ng/100.000 cells versus 10 ng/100.000 cells for lapatinib).

Encouraged by the preliminary results two key molecules with similar potency to lapatinib will undergo further evaluation in vivo to determine their pharmacokinetic characteristics using advanced mass spectrometric approaches and their efficacy in clinically relevant mouse models.

Citation Format: ARIS DOUKATAS, Efthymios-Spyridon Gavriil, Theodoros Karampelas, Panagiotis Marakos, Nicole Pouli, Constantin Tamvakopoulos. Antitumor activity of new epidermal growth factor receptor inhibitors in non-small cell lung and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-271.