3 Avenue Louis Pasteur

Boston, MA, United States

3 Avenue Louis Pasteur

Boston, MA, United States
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Lim J.,3 Avenue Louis Pasteur | Kelley E.H.,3 Avenue Louis Pasteur | Methot J.L.,3 Avenue Louis Pasteur | Zhou H.,3 Avenue Louis Pasteur | And 14 more authors.
Journal of Medicinal Chemistry | Year: 2016

The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAFV600E xenograft model. © 2016 American Chemical Society.


Lim J.,3 Avenue Louis Pasteur | Altman M.D.,3 Avenue Louis Pasteur | Baker J.,3 Avenue Louis Pasteur | Brubaker J.D.,3 Avenue Louis Pasteur | And 15 more authors.
ACS Medicinal Chemistry Letters | Year: 2015

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing. © 2015 American Chemical Society.

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