Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors

Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1)... Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors

European Journal of Medicinal Chemistry 145 (2018) 606e621 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Research paper Rational approach to highly potent and selective apoptosis signal- regulating kinase 1 (ASK1) inhibitors a, * b e e Frank Lovering , Paul Morgan , Christophe Allais , Ann Aulabaugh , c e e e d Joanne Brodfuehrer , Jeanne Chang , Jotham Coe , WeiDong Ding , Heather Dowty , b e b a e Margaret Fleming , Richard Frisbie , Julia Guzova , David Hepworth , Jayasankar Jasti , e e b a Steve Kortum , Ravi Kurumbail , Shashi Mohan , Nikolaos Papaioannou , a e a a Joseph W. Strohbach , Fabien Vincent , Katherine Lee , Christoph W. Zapf Medicine Design, Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA Inflammation and Immunology, Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA Biomedicine Design, Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA Drug Safety Research and Development, Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA Medicine Design, Pfizer, Inc., 445 Eastern Point Road, Groton, CT 06340, USA article i nf o abstract Article history: Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and Received 27 October 2017 oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal- Received in revised form regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition 11 December 2017 leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have Accepted 13 December 2017 the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver Available online 15 December 2017 diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GKþ2 position, offered opportunities for...
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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.12.041
Publisher site
See Article on Publisher Site

Abstract

Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Feb 10, 2018

References

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