DDR1-IN-2 is an effective inhibitor of the discoidin domain receptor 1 (DDR1) with an IC50 of 13.1nM. Its inhibitory effect on DDR2 is relatively weak with an IC50 of 203nM. DDR1-IN-2 also has inhibitory effects on Bcr-Abl and c-Kit, with IC50 values of 414 and 2500nM, respectively [1]. DDR is a collagen-activated receptor tyrosine kinase that plays a significant role in cell proliferation, differentiation, migration, and cell survival [2]. DDR1-IN-2 exhibits effective anti-proliferative effects on cancer cells [3].
In vitro, DDR1-IN-2 (0.625-20µM) dose-dependently inhibits the cell viability and proliferation of nasopharyngeal carcinoma cell lines, effectively suppressing the tumorigenicity of NPC cells. In CNE 2, HONE 1, CNE 1, and SUNE 1 cells, the IC50 values of DDR1-IN-2 are 1.97, 3.71, 2.06, and 3.95µM, respectively. After treating CNE 2 cells with the culture medium containing DDR1-IN-2 (2, 4 and 8μM) for 24 or 48 hours, the levels of PARP cleavage and caspase-3 activation increased [4]. Co-culturing DDR1-IN-2 (6.9, 13.8nM) with IL-1β (10ng/mL) for 3 hours significantly weakened the effect of IL-1β stimulation on cell viability at the two selected concentrations [5].
In vivo, treatment of osteoarthritis model rats with DDR1-IN-2 (6.8, 13.8nM; IA injection) in a dosing regimen of three times a week for two weeks followed by once a week for four weeks significantly improved the rats' weight-bearing capacity and running endurance, reduced chondrocyte apoptosis, promoted chondrocyte autophagy, and thereby alleviated cartilage degradation [5]. By orally administering DDR1-IN-2 (25mg/kg/d) to nude mice subcutaneously injected with MKN 28 cells for 15 days, the growth rate of tumors was significantly slowed down, and the levels of phosphorylated DDR1 and PYK2 in the tumors of mice were significantly lower than those of the control group [6].
References:
[1] Wang Z, et al. Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. ACS Med Chem Lett. 2017 Feb 9;8(3):327-332.
[2] Elkamhawy A, Lu Q, Nada H, Woo J, Quan G, Lee K. The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer. International Journal of Molecular Sciences. 2021; 22(12):6535.
[3] Matada G S P, Das A, Dhiwar P S, et al. DDR1 and DDR2: a review on signaling pathway and small molecule inhibitors as an anticancer agent[J]. Medicinal Chemistry Research, 2021, 30(3): 535-551.
[4] Lu Q P, Chen W D, Peng J R, et al. Antitumor activity of DDR1-IN-2, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells[J]. Oncology letters, 2016, 12(5): 3598-3608.
[5] Chou H-C, Chen C-H, Chou L-Y, Cheng T-L, Kang L, Chuang S-C, Lin Y-S, Ho M-L, Wang Y-H, Lin S-Y, et al. Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy. International Journal of Molecular Sciences. 2020; 21(19):6991.
[6] Hur H, Ham I H, Lee D, et al. Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma[J]. BMC cancer, 2017, 17: 1-11.
DDR1-IN-2是一种盘状结构域受体1(DDR1)的有效抑制剂，IC50为13.1nM，对DDR2的抑制效果相对较弱，IC50为203nM。DDR1-IN-2还对Bcr-Abl和c-Kit具有抑制作用，其IC50值分别为414和2500nM [1]。DDR是一种胶原激活的受体酪氨酸激酶，其在细胞增殖、分化、迁移和细胞存活中发挥显著作用 [2]。DDR1-IN-2对癌细胞表现出有效的抗增殖作用 [3]。
在体外，DDR1-IN-2（0.625-20µM）对鼻咽癌细胞株的细胞活力与增殖呈剂量依赖性抑制，有效地抑制NPC细胞的致瘤性。在CNE 2、HONE 1、CNE 1和SUNE 1细胞中，DDR1-IN-2的IC50值分别为1.97、3.71、2.06和3.95μM。用含DDR1-IN-2（2、4和8μM）的培养基处理CNE 2细胞24或48h后PARP切割和caspase-3活化水平增加 [4]。DDR1-IN-2（6.9 ，13.8nM）与IL-1β（10ng/mL）共培养处理HAC细胞3h，可显著减弱在两种选定浓度下IL-1β刺激对细胞活力的作用 [5] 。
在体内，使用DDR1-IN-2（6.8，13.8nM；IA注射）通过每周3次持续2周、而后每周1次持续4周的给药模式治疗骨关节炎模型大鼠，显著提高了大鼠的负重能力和跑步耐力，减少软骨细胞凋亡，促进软骨细胞自噬，从而减轻软骨降解 [5]。通过口服DDR1-IN-2（25mg/kg/d）治疗皮下注射MKN 28细胞的裸鼠15天，显著减缓了肿瘤的生长速度，小鼠肿瘤中的磷酸化DDR1和PYK2水平明显低于对照组的水平 [6]。