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Modulating Multi-Functional ERK Complexes by Covalent Targeting of a Recruitment Site in Vivo

Modulating Multi-Functional ERK Complexes by Covalent Targeting of a Recruitment Site in Vivo

Tamer S Kaoud, William H Johnson, Nancy D Ebelt, Andrea Piserchio, Diana Zamora-Olivares, Sabrina X Van Ravenstein, Jacey R Pridgen, Ramakrishna Edupuganti, Rachel Sammons, Micael Cano, Mangalika Warthaka, etc.

Nat Commun. 2019 Nov 19;10(1):5232.

PMID: 31745079

Abstract:

Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the active site and mediates ERK-protein interactions. We demonstrate that the small molecule BI-78D3 binds to the DRS of ERK2 and forms a covalent adduct with a conserved cysteine residue (C159) within the pocket and disrupts signaling in vivo. BI-78D3 does not covalently modify p38MAPK, JNK or ERK5. BI-78D3 promotes apoptosis in BRAF inhibitor-naive and resistant melanoma cells containing a BRAF V600E mutation. These studies provide the basis for designing modulators of protein-protein interactions involving ERK, with the potential to impact ERK signaling dynamics and to induce cell cycle arrest and apoptosis in ERK-dependent cancers.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP883065905-A	BI-78D3		883065-90-5	Price

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