European Journal of Medicinal Chemistry (2021)
Update date:2022-08-15
Topics:
Huang, Minhao
Huang, Yongjun
Guo, Jing
Yu, Lei
Chang, Yu
Wang, Xiaolu
Luo, Jinfeng
Huang, Yanhui
Tu, Zhengchao
Lu, Xiaoyun
Xu, Yong
Zhang, Zhimin
Zhang, Zhang
Ding, Ke
A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a Kd value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. The compound also potently inhibited the kinase activity of TTK with an IC50 value of 23 nM, induced chromosome missegregation and aneuploidy, and suppressed proliferation of a panel of human cancer cell lines with low μM IC50 values. Compound 5o demonstrated good oral pharmacokinetic properties with a bioavailability value of 45.3% when administered at a dose of 25 mg/kg in rats. Moreover, a combination therapy of 5o with paclitaxel displayed promising in vivo efficacy against the HCT-116 human colon cancer xenograft model in nude mice with a Tumor Growth Inhibition (TGI) value of 78%. Inhibitor 5o may provide a new research tool for further validating therapeutic potential of TTK inhibition.
View MoreKaiping Genuine Biochemical Pharmaceutical Co.,Ltd.
Contact:+86-750-2881198
Address:No.1, Xinke Road, Shatang Town, Kaiping, Guangdong Province, P.R.China
lianyungang jinkang pharmaceutical technology co., ltd.
Contact:008651885445517
Address:Jinshan industrial park, Ganyu county, Lianyungang, Jiangsu Province, 222115, China
Contact:86-170-000000
Address:No.168 Road,han city, China
Contact:86-512-87182055
Address:No.128 Fangzhou Rd, Suzhou Industrial Park, China, 215125, China
Contact:+(852) 301-98033
Address:Flat C, 23/F, Lucky Plaza, 315-321 Lockhart Road, Wan Chai, Hong Kong
Doi:10.1002/aoc.4098
(2018)Doi:10.1021/ja01863a008
(1940)Doi:10.1039/c3ce42449a
(2014)Doi:10.1016/S0040-4039(00)60440-9
(1993)Doi:10.1246/bcsj.61.2690
(1988)Doi:10.1002/jps.2600730332
(1984)