DDR1-IN-2 is a selective DDR1 inhibitor with IC50 value of 6.8nM in an enzymatic activity assay. It exhibited less inhibitory effect on DDR2 with IC50 value of 101.4nM. DDR1-IN-2 dose-dependently inhibited phosphorylation of DDR1 in NCI-H23 non-small cell lung cancer cells (NSCLC) expressing high level of DDR1 at doses of 0.5, 1 and 2μM. The inactivation of DDR1 by DDR1-IN-2 induced significant decrease of total protein levels of Bcl-xL and MMP-2. It suppressed the growth of A549, NCI-H23 and NCI-H460 human NSCLC cells with IC50 values of 2.7, 2.1 and 3.0μM, respectively, while the value in K562 human CML cells was approximately 0.038μM. Also it inhibited colony formation by NCI-H23 NSCLC cells with IC50 values of 0.56 and 3.29 μM, respectively. DDR1-IN-2 potently inhibited cell-matrix adhesion by ~17%, ~40% or ~88% at 5.0, 10.0 or 20.0 μM for 2 hours, respectively, as well as inhibited the invasiveness of NCI-H23 cells by ~30%, ~37% or ~82% at 1.0, 2.0 or 5.0 μM for 24 hours, respectively. DDR1-IN-2 possessed good PK profiles with oral bioavailability of 67.4%[2].
作用机制
DDR1-IN-2 tightly binds to the ATP-binding site of DDR1. It inhibited DDR1 in a competitive manner.[2]
7rh 细胞实验
Cell Line
Concentration
Treated Time
Description
References
93T449 cells
0.00002-10 μM
5 days
To evaluate the effect of 7RH on liposarcoma cell growth and proliferation, results showed that 7RH reduced cell growth and proliferation
Clin Orthop Relat Res. 2023 Nov 1;481(11):2140-2153
SW 872 cells
0.00002-10 μM
5 days
To evaluate the effect of 7RH on liposarcoma cell growth and proliferation, results showed that 7RH reduced cell growth and proliferation
Clin Orthop Relat Res. 2023 Nov 1;481(11):2140-2153
MKN28 cells
0.18, 0.54, 1.62 μM
Inhibited phosphorylation of DDR1 and PYK2, reduced colony formation and migration
BMC Cancer. 2017 Jan 31;17(1):87
KATO-III cells
0.18, 0.54, 1.62 μM
Inhibited phosphorylation of DDR1 and PYK2, reduced colony formation and migration
BMC Cancer. 2017 Jan 31;17(1):87
KB cells
3μM
3 h
Enhanced cytotoxicity of RG7787, IC50 reduced from >100 ng/ml to 6 ng/ml
Cancer Res. 2016 Mar 15;76(6):1560-8
UM cells (92.1, Mel270)
10 μM
48 h
To evaluate the effect of 7rh on ALDH activity in UM cells, results showed that 7rh significantly reduced the percentage of ALDH+ cells
Signal Transduct Target Ther. 2021 May 12;6(1):176
UM cells (92.1, Mel270)
15 μM
24-48 h
To evaluate the effect of 7rh on UM cell apoptosis, results showed that 7rh induced apoptosis in UM cells, as evidenced by PARP cleavage and caspase-3 activation
Signal Transduct Target Ther. 2021 May 12;6(1):176
UM cells (92.1, Mel270, Omm1, Omm2.3)
0-20 μM
48 h
To evaluate the effect of 7rh on UM cell proliferation, results showed that 7rh concentration-dependently inhibited UM cell growth with IC50 values ranging from 4 to 10 μM
Signal Transduct Target Ther. 2021 May 12;6(1):176
7rh 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c-nu nude mice
MKN28 xenograft model
Oral
25 mg/kg
Every 2 days for 15 days
Suppressed tumor growth, reduced phosphorylation of DDR1 and PYK2
BMC Cancer. 2017 Jan 31;17(1):87
Nude mice
Subcutaneous xenograft model in nude mice
Intraperitoneal injection
8 mg/kg
Once daily for 20 days
To evaluate the inhibitory effect of 7RH on the growth of nasopharyngeal carcinoma tumors in vivo. The results showed that 7RH could significantly inhibit tumor growth
Oncol Lett. 2016 Nov;12(5):3598-3608
Athymic nude mice
A431/H9 and KLM1 xenograft models
Oral gavage
10 or 20 mg/kg 7rh
Daily for a total of 16 doses
Combination of 7rh and RG7787 significantly enhanced antitumor activity, with 61% reduction in A431/H9 tumor volume and 89% reduction in KLM1 tumor volume
Cancer Res. 2016 Mar 15;76(6):1560-8
BALB/c mice
MSS CRC mouse model
Oral
12.5 mg/kg
Every three days, three times in total
To evaluate the effect of 7rh in combination with PD-1 blockade
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