Design and optimisation of Proto-Oncogene Tyrosine Kinase SRC antagonists based on the novel ECF506 scaffold

Abstract

Proto-oncogene tyrosine-protein kinase (SRC) is highly expressed in triple-negative breast cancer where it promotes tumorigenesis by amplifying mitogenic signalling pathways. The activity of SRC is enhanced through phosphorylation at Try416, which stabilizes an activation loop permitting substrate binding. Fraser et al, 2016 indicated that ECF506 supresses SRC activity at sub-nanomolar levels through inhibition of phosphorylation at Tyr416.

PDB5J5S describing SRC bound to a sulphonamide inhibitor was recruited. Virtual screening and in silico de-novo approaches were employed to identify molecular hits and design novel ligands capable of modulating SRC at the ligand binding pocket (LBP). Virtual screening using a structure-based consensus pharmacophore of the lead ECF506 and the cognate sulphonamide inhibitor yielded a series of lead-like molecules which were filtered for Lipinski rule compliance, docked into the protomol of the target SRC and ranked according to their physiochemical properties and ligand binding affinity (LBA).

In the de novo approach seed fragments where designed based on topology maps of the lead ECF506 and the sulphonamide inhibitor. Seed fragments were able to sustain molecular growth at pre-designated growing sites generating Lipinski complaint de novo ligands. The generated ligands were docked into the SRC-LBP and ranked in order of LBA towards the LBP. The critical interactions forged between highest ranking hits and the SRC-LBP were studied.