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J Med Chem. 2018 Apr 26;61(8):3516-3540. doi: 10.1021/acs.jmedchem.7b01795. Epub 2018 Mar 29.

Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition.

Author information

1
eFFECTOR Therapeutics , 11180 Roselle Street , San Diego , California 92121 , United States.
2
Primmune Therapeutics, Inc. , 3210 Merryfield Row , San Diego , California 92121 , United States.
3
Structure-Based Design, Inc. , 6048 Cornerstone Court West #D , San Diego , California 92121 , United States.
4
Molecular Stethoscope , 10835 Road to the Cure #100 , San Diego , California 92121 , United States.
5
Department of Chemistry , University of Pennsylvania , 231 South 34th Street , Philadelphia , Pennsylvania 19104 , United States.
6
Oncternal Therapeutics , 3525 Del Mar Heights Road #821 , San Diego , California 92130 , United States.
7
Molcentrics, Inc. , 11835 Carmel Mountain Road #1304-110 , San Diego , California 92128 , United States.
8
Abide Therapeutics , 10835 Road to the Cure, Suite 250 , San Diego , California 92121 , United States.
9
Polaris Pharmaceuticals , 9373 Towne Centre Drive #150 , San Diego , California 92121 , United States.

Abstract

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

PMID:
29526098
DOI:
10.1021/acs.jmedchem.7b01795
[Indexed for MEDLINE]

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