title: Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.
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.
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Ildiko M
authors.initials: IM
authors.lastname: Buck
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Carr
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Anne
authors.initials: A
authors.lastname: Cleasby
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Coyle
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Jayne E
authors.initials: JE
authors.lastname: Curry
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: James E H
authors.initials: JE
authors.lastname: Day
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Day
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Keisha
authors.initials: K
authors.lastname: Hearn
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Aman
authors.initials: A
authors.lastname: Iqbal
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Lydia Y W
authors.initials: LY
authors.lastname: Lee
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mortenson
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Munck
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Lee W
authors.initials: LW
authors.lastname: Page
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Sahil
authors.initials: S
authors.lastname: Patel
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Susan
authors.initials: S
authors.lastname: Roomans
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Smith
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Tamanini
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
authors.forename: Gordon
authors.initials: G
authors.lastname: Saxty
keywords: back to front kinase design; discoidin domain receptor; fragment-based drug design