Zechariah G Marting
The University of
Sydney
Australia
Title: Targeting the ‘Oligomerization Region’ of the Epidermal Growth Factor Receptor (EGFR) Using Small Molecules as Novel Anticancer Agents
Biography
Biography: Zechariah G Marting
Abstract
The chemotherapy of human cancer in modern times still faces enormous challenges for its complexity, resistance, and absence of an integral molecular operation that targets any known group of the malady [1, 2] at once. EGFR (ErbB1/HER1) and its subfamily members ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) exhibit the most crosstalk of signalling among themselves and other paths [3] and are crucial to regulating cell proliferation, apoptosis, migration, differentiation and survival, following activation and induced conformational change by a cognate ligand such as EGF, which then undergoes an oligomerization process in the oligomerization region. In aberrancy, EGFR, as an archetypal of the subfamily most studied is a most featured receptor in several solid carcinomas such as breast and NSCLC, occurring as homo- or hetero-oligomers (dimer or tetramer) [4-6]. Fewer small molecules have been developed to target the region that influences significantly the downstream signal transduction, for instance, via posttranslational modification of proteins that causes auto-trans-phosphorylation of tyrosine residues the downstream signal cascades depend on. LigPrep (version 3.0, 2014-4) and Epik (version 3.0, 2014-4) on Maestro (Version 9.8, 2014) as the graphical use interface of the Schrodinger Suite (Schrodinger Inc., NY, USA), were utilized to design lead candidates 3-(furan-2-yl)-4-(8-hydroxyquinolin-2-yl)-1,4,6,7-tetrahydro-5Hpyrazolo[ 3,4-c]pyridin-5-one (IC50 = 0.13nM); 3,3,3-trifluoro-2-hydroxy-N-((2-(4 methylpiperazin-1-yl)pyridin-3-yl)methyl)propanamide (IC50 = 33.42nM); 2-((2-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)quinolin-8-ol (IC50 = 3.05μM) and 5-(1-cyclopentylpyrrolidin-2-yl)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (IC50 = 0.32μM) lead molecules that target the oligomerization region. Two novel compounds 2-hydroxy-N-(4-hydroxybenzyl)-2-(4-hydroxyphenyl) acetamide, had potent antioligomerization activity (IC50 = 0.63 μM) and N'1,N'2-dicyclopentylideneoxalohydrazide (not yet bio evaluated) were synthesized on optimization of lead candidates using Combiglide (version 3.5, 2014-4).