Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy |
| |
| Authors: | Lingzhi Zhang Qiurong Ju Jinjin Sun Lei Huang Shiqi Wu Shuping Wang Yin Li Zhe Guan Qihua Zhu Yungen Xu |
| |
| Affiliation: | 1.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; (L.Z.); (Q.J.); (J.S.); (L.H.); (S.W.); (S.W.); (Y.L.); (Z.G.);2.Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China |
| |
| Abstract: | Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors. |
| |
| Keywords: | ERK inhibitor PI3K inhibitor dual ERK/PI3K inhibitors cross-talk |
|
|
