Research Projects

The drug development paradigm has been improved over the last decade by introducing new modalities for targeting the protein of interest. All the approved EGFR-TKIs failed to treat the resistance issues after a certain period of their use. Like different cancer targets, EGFR has also been targeted for degradation by PROTACs. However, very few studies have been reported so far. These PROTACs can degrade different mutant EGFRs like EGFRdel19, EGFRL858R, and EGFRT790M/L858R without affecting EGFRWT. Thus this approach can effectively overcome the selectivity as well as resistance issues of the traditional inhibitors. Recently we discovered 6b as the most potent EGFR inhibitor and the funding of this work was supported by SERB-Department of Science and Technology (DST), Delhi (EMR/2017/002702). The compound 6b showed a great anti-proliferative effect on H1975 (Harboring L858R/T790M double mutation) lung cancer cells, reduced oxidative stress, and altered mitochondrial membrane potential further leading to apoptosis and induces cell cycle arrest in A549 lung cancer cells at G-phase. 6b alone significantly suppressed tumour volume, especially at the high dose of 30mg/kg. The present research proposal involves the design, synthesis, in-vitro & in-vivo assessment of PROTAC molecules for targeting EGFR. These designed PROTAC includes the 6b derived EGFR inhibitor as EGFR binding moiety and modified thereof to attach linker subsequently. As compound 6b has better EGFR inhibitory activity than gefitinib, the designed PROTACs are expected to degrade the mutant EGFR and offer a potential modality to overcome the resistance issue. Further, SciFinder database search reveals that the proposed EGFR PROTACs are novel and can be patented.