The mitogen-activated protein kinase (MAPK) pathway, consisting of Ras-Raf-MEK-ERK arranged in a cascade, promotes cellular proliferation and survival. Changes within this pathway resulting in its deregulation frequently occur in human cancer. Efforts have been made to identify selective inhibitors of BRAF and MEK for treatment of BRAF-mutant melanoma. However, acquired drug resistance through ERK reactivation represents a significant challenge for these current therapies. Recently, ERK has emerged as a potential therapeutic target. We have previously identified I-1+ as a potent covalent inhibitor of the activation and activity of ERK in A375 melanoma cells. Here, we report the design and synthesis of a small-molecule which combines the ability to covalently inhibit ERK with the ability to induce its degradation using PROTAC (Proteolysis Targeting Chimera) technology. Preliminary data provide a compelling rationale for the development of ERK PROTACs based on our lead compound I-1+. Further functionalization of I-1+ to induce cellular degradation of ERK was accomplished by linking it to the E3 ligase Cereblon ligand pomalidomide using established peptide coupling reagents. The placement of this ligand was guided by docking I-1+ into our available x-ray structure of ERK to identify solvent-exposed sites. Initial studies demonstrate that our covalent ERK PROTAC degrades ERK at concentrations as low as 1 µM in the BRAFV600E mutant A375 melanoma cell line. Further evaluation of the mechanism-of-action and selectivity is expected to yield an ERK PROTAC that can degrade ERK at concentrations of 100 nM or below, exhibits cellular potency for ERK, and inhibits downstream signaling to p90RSK. As ERK reactivation represents a significant mechanism of resistance to current treatments in melanoma, ERK PROTACs have the potential to represent a new paradigm for inhibiting ERK signaling, as well as overcoming resistance.

Design, synthesis, and evaluation of small molecule PROTACs to induce ERK degradation

2019 Fall National Meeting

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