Discovery and Optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors

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.

Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1

“…The specific inhibitor 7rh (22) inhibited collagen I-dependent up-regulation of N-cadherin (Fig. 3f), consistent with the results we obtained with 1NM-PP1 and the gatekeeper mutant form of DDR1b (Fig.…”

“…Recently small molecule inhibitors specifically targeting the kinase activity of DDR1 have been developed (20,21). Importantly, the DDR1-specific inhibitor 7rh (22) inhibited collagen-I induced N-cadherin up-regulation in pancreatic cancer cells (Fig. 3f).…”

“…Collagen I-coated dishes and rat tail collagen I were obtained from BD Biosciences. The synthesis of the DDR1-specific inhibitor 7rh has been described (22).…”

Extracellular matrix component signaling in cancer

“…Inhibitors originally developed to target the activity of BCR-ABL kinase are also potent inhibitors of the DDRs [143,144], but these drugs have a very broad specificity and are active against a number of additional kinases. Orally bioavailable small molecule kinase inhibitors with selectivity over other kinases have been developed for DDR1 and DDR2 [126,[145][146][147]. However, since kinase-independent functions have been discovered for DDR1, in particular its essential role in collective cancer cell migration and invasion [110], DDR-selective kinase inhibitors may not be effective against all DDR-dependent roles in disease progression.…”

Antitumor activity of 7RH, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells

“…Therefore, the present study aimed to investigate the effects of a (3-(2-(pyrazolo(1,5-a) pyrimidin-6-yl)-ethynyl)benzamide compound, 7RH (Fig. 1A), which is a potent and reversible small molecule inhibitor of DDR1 (28), on the proliferation and apoptosis of NPC cells, as well as the underlying mechanisms of such. In addition, the ability of 7RH to act synergistically with the SFK inhibitor, dasatinib, was evaluated.…”