| Literature DB >> 26191369 |
Christopher W Murray1, Valerio Berdini1, Ildiko M Buck1, Maria E Carr1, Anne Cleasby1, Joseph E Coyle1, Jayne E Curry1, James E H Day1, Phillip J Day1, Keisha Hearn1, Aman Iqbal1, Lydia Y W Lee1, Vanessa Martins1, Paul N Mortenson1, Joanne M Munck1, Lee W Page1, Sahil Patel1, Susan Roomans1, Kirsten Smith1, Emiliano Tamanini1, Gordon Saxty1.
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.Entities:
Keywords: back to front kinase design; discoidin domain receptor; fragment-based drug design
Year: 2015 PMID： 26191369 PMCID： PMC4499826 DOI： 10.1021/acsmedchemlett.5b00143
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345