- Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis
-
The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.
- Zhang, Weihe,McIver, Andrew L.,Stashko, Michael A.,Deryckere, Deborah,Branchford, Brian R.,Hunter, Debra,Kireev, Dmitri,Miley, Michael J.,Norris-Drouin, Jacqueline,Stewart, Wendy M.,Lee, Minjung,Sather, Susan,Zhou, Yingqiu,Di Paola, Jorge A.,Machius, Mischa,Janzen, William P.,Earp, H. Shelton,Graham, Douglas K.,Frye, Stephen V.,Wang, Xiaodong
-
-
Read Online
- THERAPUETIC USES OF SELECTED PYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
-
Uses of pyrimidines with anti-Mer tyrosine kinase activity as anti-infective agents, immunostimulatory and immunomodulatory agents, anti-cancer agents (including against MerTK -/- tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.
- -
-
Page/Page column 168
(2015/11/03)
-
- PYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER
-
Described are compounds of Formula I or Formula II: wherein: ring A is a 5- or 6-membered heteroaryl group; dashed lines are optional double bonds; X is N or O; Y is a carbon atom or an S or N heteroatom in ring A in any suitable location; and substituents are as given herein. Compositions containing the same and methods of using the same in treating cancers such as acute lymphoblastic leukemia are also described.
- -
-
Page/Page column 35; 36; 53
(2014/01/07)
-
