Dataset to Project NCN PRELUDIUM 20 UMO-2021/41/N/ST4/00059

Abstract

Lung cancer remains a deadly disease with very limited treatment options and poor prognosis. Efforts in anti-lung cancer drugs development resulted in a discovery of the epidermal growth factor receptor thymine kinase domain (EGFR TK) inhibitors. The key representative of these drugs is erlotynib (TarcevaTM). Erlotynib belongs to the group of synthetic 4-anilinoquinazoline TK inhibitors. It binds to mutated TK domain of EGFFR at ATP binding site in close proximity to catalytically key lysine745 (K745) residue. The nitrogen atom-N1 of the erlotynib acts as acceptor of H-bond from Met769 residue whereas the second quinazoline N atom interacts with Thy766 via water molecule. The triple bond of erlotynib fill in the empty pocket with the closest amino acid residues of Thr766, Lys721 and Leu764 being ca. 4 Å away. Posing of the tripe bond in a relatively empty space offers possibilities in its functionalization with more bulky groups. After inhibition of TK by erlotynib the downstream signaling cascades are halted along with proliferation of the cell what is a molecular basis of anticancer (antiproliferative) action for EGFR TK inhibitors. Unfortunately due to specific mutations e.g. in Exon 19, 18 and 21 erlotynib-treated lung adenocarcinomas lost sensitivity toward drug what cause disease progression with no options for further successful pharmacotherapy treatment. Literature survey shows that to date there is only one report published in 2020 which focus on organometallic erlotynib derivative bearing gold (I) center. It shows greater anticancer activity than erlotynib alone and differ in terms of action mode. In grant we devise hypothesis that erlotynib-resistance of mutated lung cancer cells can be overcome by organometallic erlotynib derivatives. Two classes of these molecules were obtained via cycloaddition reactions in the frame of the project: A) the phosphorescent [Re(μ-Cl)2(CO)6(μ-pydz)] (pydz = 1,2-pyridazine) derivatives and B) the ferrocenyl, ruthenocenyl and cymantrenyl “click” derivatives. After characterization with a spectroscopic methods obtained compounds were subjected toward anticancer activity studies against panel of non-small cell lung cancer cells (NSCLC) Mechanism of action of the most active compounds were examined by a battery of biological assays. The data below is the result of the implementation of a grant financed by the National Science Centre in Cracow,Poland (Preludium 20 grant UMO-2021/41/N/ST4/00059).