Dataset Information

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.

SUBMITTER: Murray CW

PROVIDER: S-EPMC4499826 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.

Murray Christopher W CW Berdini Valerio V Buck Ildiko M IM Carr Maria E ME Cleasby Anne A Coyle Joseph E JE Curry Jayne E JE Day James E H JE Day Phillip J PJ Hearn Keisha K Iqbal Aman A Lee Lydia Y W LY Martins Vanessa V Mortenson Paul N PN Munck Joanne M JM Page Lee W LW Patel Sahil S Roomans Susan S Smith Kirsten K Tamanini Emiliano E Saxty Gordon G

ACS medicinal chemistry letters 20150604 7

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 th ...[more]

PMID: 26191369

Dataset Information

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.

Publications

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.

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