Fragment-based discovery of potent and selective DDR1/2 inhibitors

DOI: 10.1021/acsmedchemlett.5b00143
PMID: 26191369

Authors: Christopher W. Murray (Astex Pharmaceuticals) , Valerio Berdini (Astex Pharmaceuticals) , Ildiko M. Buck (Astex Pharmaceuticals) , Maria E. Carr (Astex Pharmaceuticals) , Anne Cleasby (Astex Pharmaceuticals) , Joseph E. Coyle (Astex Pharmaceuticals) , Jayne E. Curry (Astex Pharmaceuticals) , James E. H. Day (Astex Pharmaceuticals) , Phillip J. Day (Astex Pharmaceuticals) , Keisha Hearn (Astex Pharmaceuticals) , Aman Iqbal (Astex Pharmaceuticals) , Lydia Y. W. Lee (Astex Pharmaceuticals) , Vanessa Martins (Astex Pharmaceuticals) , Paul N. Mortenson (Astex Pharmaceuticals) , Joanne M. Munck (Astex Pharmaceuticals) , Lee W. Page (Astex Pharmaceuticals) , Sahil Patel (Astex Pharmaceuticals) , Susan Roomans (Astex Pharmaceuticals) , Kirsten Smith (Astex Pharmaceuticals) , Emiliano Tamanini (Astex Pharmaceuticals)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 6 (7) , PAGES 798 - 803

State: Published (Approved)
Published: July 2015

Abstract: The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the “back-to-front” design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

Journal Keywords: Selectivity; Kinase inhibitors; Peptides and proteins; Molecules; Inhibitors

Diamond Keywords: Lung Cancer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 18/11/2015 14:11

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)