Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells

Abstract

The RAF/MEK/ERK pathway is a crucial signal path which is closely associated with the proliferation, differentiation, and apoptosis of tumors. MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem. Most of the inhibitors possess a similar diarylamine scaffold. Here we designed and synthesized a series of MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor. P6b among them showed the most potent degradation effect, with DC 50 values of 0.3 μM and 0.2 μM in MEK1 and MEK2 degradation, respectively. An antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC 50 = 2.8 μM) compared to A549 cells (IC 50 = 27.3 μM). To sum up, we discovered P6b with a non-diarylamine scaffold for the first time as a potent MEK PROTAC effective in human cancer cells.

Lithium salt of a pro-mesogenic [closo-CB11H12]− derivative: anisotropic Li+ ion transport in liquid crystalline electrolytes

“…The use of DCC instead of EDC·HCl for the synthesis of 2F[4] resulted in contamination of the product with urea byproducts, which were difficult to remove. The requisite ditosylates 4[ n ] were prepared according to a general procedure 51 and full procedures and analytical data are listed in the ESI †…”

“…Dalton Transactions cedure 51 and full procedures and analytical data are listed in the ESI. † The pro-mesogenic ionic additive S2 [Li] was prepared as shown in Scheme 2.…”

Syntheses, reactivity, and biological applications of coumarins

“…Even if several MEK1/2 inhibitors were reported, acquired resistance remains a significant problem. Xu and co-workers designed and synthesized a series of coumarin-based MEK1/2 PROTAC MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor effective in human cancer cells ( Wang et al, 2023 ). 216 is the most promising derivative showing a DC 50 values of 0.3 and 0.2 μM in MEK1 and MEK2 degradation, respectively.…”

Possible correlated signaling pathways with chronic urate nephropathy: A review

“…Affected by upstream protein signals, signals can be transferred from the cytoplasm to the nucleus, such as RAS, [30] RAF, [31] MEK. [32] Furthermore, it mediates the transcriptional activation of downstream proteins and participates in cell proliferation and differentiation, senescence and apoptosis, [33] such as Elk-1, [34] ATF [35] , and Ap-1. [36] Liu [37] observed the changes of glomeruli and renal interstitium by increasing ERK1/2 phosphorylation in the HN rat model, and found that the pharmacological targeting of ERK2/1 can alleviate HN by inhibiting TGF-βsignal transduction, reducing inflammatory response and inhibiting molecular processes associated with elevated serum UA levels in the body.…”