Targeting the ‘Oligomerization Region’ of the Epidermal Growth Factor Receptor using Small Molecule Inhibitors as Novel Anticancer Agents

Abstract

There are two main types of ErbB-RTK subfamily inhibitors, viz, a) the mAbs and b) the RTKIs, which act at different domains of the receptors. The mAbs act at the ectodomain locale either by interfering with the ligand such as EGF or the receptor such as EGFR, in each case interference with dimerization occurs. The RTKIs inhibit numerous biochemical processes beginning with the recruitment of accessory proteins by the dimerized complexes. However, little has been done specifically in the ‘oligomerization region’ in developing active anti-EGFR anti-oligomeric small molecules that can inhibit the oligomerization processes in spite the ligands are bound to their canonical ErbB receptors. The concept of the oligomerization mechanisms, particularly heterotetramerization, has shown leading clues to untangle some of the probes dimerization has limited explanations for, wherein lies the scope of our work. We have designed four small molecules, namely, 3-(furan-2-yl)-4-(8-hydroxyquinolin-2-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one (%IG50,3.98 µM; %IC50, 8.90 µM), 3,3,3-trifluoro-2-hydroxy-N-((2-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)propanamide (%IG50, 0.25 µM; %IC50, 0.40 µM), 2-((2-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)quinolin-8-ol (%IG50, 1.59 µM; %IC50, 1.50 µM) and 4-(1-cyclopentylpyrrolidin-2-yl)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (%IG50, 1.59 µM; %IC50, 1.10 µM) that act at the ‘oligomerization region’, using the Schrodinger Software v10.4Maestro, v6.9Glide (Schrödinger, LLC, New York, NY, 2015-4) on scrutinizing ≥ 9 x 106 ligands from different chemical databases.