Identification of Multi-kinase Allosteric Inhibitors of Oncogenic Targets EGFR1, PI3K, and BRAF Kinase

This study aimed to identify promising allosteric inhibitors with the potential to inhibit EGFR1, PI3K, and BRAF kinases as a single agent or in a combination of existing drugs, thus acting as a therapeutic option when traditional drugs fail to give a beneficial response in disease pathology.Upregulation of EGFR1 activates several downstream signaling pathways, resulting in pathophysiological alterations that contribute to cancer. The RAS/RAF/MEK/ERK (MAPK) and PI3K/Akt/mTOR (PI3K/Akt/mTOR) pathways are major downstream signalling partners induced by EGFR1 activation. Despite their vast importance, allosteric FDA-approved drugs targeting EGFR1 and these pathways are not available.The objective of the study is to identify novel multi-kinase small molecules with the potential to inhibit major sites of amplification of cancer signalling pathways, i.e., EGFR1, PI3K/Akt/mTOR, and RAS/RAF/MEK/ERK (MAPK) signalling pathways targeting allosteric sites.In silico methods were used to identify the potential inhibitors using EGFR1, PI3, and BRAF crystal structures complexed with allosteric inhibitors. The potential novel molecules were confirmed for their drug-likeness. Their stability of binding was also confirmed using molecular dynamics simulation studies. To eliminate false negatives, this study used a pharmacophore and structure-based targeting method.The current study was effective in identifying drug-like small molecules, such as ZINC38783966, ZINC01456629, ZINC01456628, and 124173751, 137352549, 137353176, 137352399, 132020316 from ZINC and PubChem database, respectively, with a potential to bind EGFR1 (6DUK), PI3 (4A55) and BRAF (6P3D) at allosteric sites. A 50 ns molecular dynamics investigation also revealed that these potential novel multitarget kinase allosteric inhibitors exhibited stable binding.Alterations in EGFR1, PI3K/Akt/mTOR, and RAS/RAF/MEK/ERK (MAPK) signalling pathways are observed in cancers in high frequency and are also used by viral and environmental toxicants for pathologic purposes. These multi-kinase allosteric inhibitors will provide insight into allosteric drug discovery and deepen our understanding of targeting these pathways, either individually or in combination with orthosteric inhibitors.