Discovery of pyrazolo[3,4-b]pyridine derivatives as novel and potent Mps1 inhibitors for the treatment of cancer

Eur J Med Chem. 2023 May 5:253:115334. doi: 10.1016/j.ejmech.2023.115334.

Shihe Hu ¹, Cuihua Jiang ², Meng Gao ², Dongjian Zhang ², Nan Yao ², Jian Zhang ³, Qiaomei Jin ⁴

Affiliations

1 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China; SkyRun Pharma Co., Ltd., No. 9 Weidi Road, Nanjing, 210046, PR China.
2 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
3 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China. Electronic address: [email protected].
4 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China. Electronic address: [email protected].

PMID: 37037136 DOI: 10.1016/j.ejmech.2023.115334

Abstract

Monopolar spindle kinase 1 (Mps1) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors. With this aim, a set of pyrazolo[3,4-b]pyridine-based compounds as new Mps1 inhibitors was investigated through a multidisciplinary approach, based on virtual screening, chemical synthesis and biological evaluation. One of the representative compounds, 31, exhibited strong kinase inhibitory potency against Mps1 with an IC₅₀ value of 2.596 nM and significantly inhibited proliferation of Cancer cells, especially MDA-MB-468 and MV4-11 cells. Compound 31 also displayed reasonable kinome selectivity against a panel of 606 wild-type kinases at 1 μM. Moreover, compound 31 exhibited suitable preclinical pharmacokinetic parameters and a promising pharmacodynamic profile. Further, compound 31 showed good antitumor efficacy in MDA-MB-468 xenograft model with no obvious toxicity. Overall, compound 31 was identified as a potential Mps1 Inhibitor for Cancer therapy and deserve further research.

Keywords

Cancer; Kinase inhibitor; Monopolar spindle kinase 1 (Mps1); Pyrazolo[3,4-b]pyridine; Synthesis.

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