Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023)

Synthesis and biological research of new imidazolone-sulphonamide-pyrimidine hybrids as potential EGFR-TK inhibitors and apoptosis-inducing agents

“…EGFR-TK is a well-known and validated anticancer target with several clinically used drugs. 34 To examine the potential mechanism falling behind the high anticancer effects of imidazolone-sulphonamide-pyrimidine hybrids, the inhibitory potential was evaluated against EGFR-TK. The most effective cytotoxic hybrid molecules 5h, 5j and 6b were assessed for their suppressive efficacy against EGFR-TK.…”

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

“…However, new approaches are being developed to increase specificity, avoid the RAF paradox effect of current RAF inhibitors, and reduce potential toxicity (see, for example, [13]). A key step forward in drug development is the use of PROTACs (proteolysis targeting chimeras) that combine a small molecule inhibitor of the protein of interest with an E3 ubiquitin ligase binder, resulting in ubiquitinylation of the target protein that is then degraded by the proteasome [45]. One advantage is that the target is degraded, which theoretically avoids problems of * [25] * [111] * [112] ** [113] ** [114] ** [115] ** [115] incomplete inhibition and, for RAF kinases, potential paradoxical activation of ERK1/2 signalling (although as we discuss below, this is not necessarily the case).…”

“…There is considerable excitement about the development of PROTACs for enzyme degradation [45], as discussed above. The likely effects of PROTAC drugs as a whole, irrespective of their protein target, on cardiomyocytes and the heart are impossible to predict.…”