Abstract:
:Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the enzymatic activity of DDR1, with IC50 values of 6.8 and 7.0 nM, respectively, but were significantly less potent in suppressing the kinase activities of DDR2, Bcr-Abl, and c-Kit. Further study revealed that 7rh bound with DDR1 with a Kd value of 0.6 nM, while it was significantly less potent to the other 455 kinases tested. The S(35) and S(10) selectivity scores of 7rh were 0.035 and 0.008, respectively. The compounds also potently inhibited the proliferation of cancer cells expressing high levels of DDR1 and strongly suppressed cancer cell invasion, adhesion, and tumorigenicity. Preliminary pharmacokinetic studies suggested that they possessed good PK profiles, with oral bioavailabilities of 67.4% and 56.2%, respectively.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gao M,Duan L,Luo J,Zhang L,Lu X,Zhang Y,Zhang Z,Tu Z,Xu Y,Ren X,Ding Kdoi
10.1021/jm301824ksubject
Has Abstractpub_date
2013-04-25 00:00:00pages
3281-95issue
8eissn
0022-2623issn
1520-4804journal_volume
56pub_type
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