A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 μM) as compared to gefitinib (IC50 > 20 μM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Imidazole-based epidermal growth factor receptor (EGFR) inhibitors were computationally designed and synthesized.

Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design.

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