Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy.

Lingzhi Zhang,Qihua Zhu,Jinjin Sun,Yungen Xu,Yin Li,Qiurong Ju,Shiqi Wu,Shuping Wang,Zhe Guan,Lei Huang

doi:10.3390/molecules25235693

Lingzhi Zhang, Qihua Zhu + Show 8 more

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https://doi.org/10.3390/molecules25235693

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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.

Highlights

Numerous small molecule kinase inhibitors have become an effective methods for the treatment of cancer, due to their good selectivity, high potency and low toxicity
In the process of investigating existing PI3K inhibitors, we found that a urea-based with
Nitrogen-containing heterocycle was often introduced into PI3K inhibitors, such as compound 4

Summary

Introduction

Numerous small molecule kinase inhibitors have become an effective methods for the treatment of cancer, due to their good selectivity, high potency and low toxicity. Because of drug resistance, the clinical benefits of small molecule kinase inhibitors have been greatly limited [1]. The resistance mechanism can be divided into two categories: one is from the overexpression and resistance mutations of the target kinase itself (on-target); the other is not directly related to the target itself, but through alternative signaling pathways to achieve resistance (by-pass) [2]. In addition to the continuous development of new kinase inhibitors targeting mutation sites, the drug resistance could be better overcome by inhibiting related bypass signaling pathways. There are some drawbacks of drug combination, such as incompatible PK, enhanced toxicity, or even causing drug-induced diseases and threatening life. Multi-target drugs simultaneously act on multiple targets to exert a synergistic effect, and reduce the dosage of drugs, avoiding the Molecules 2020, 25, 5693; doi:10.3390/molecules25235693 www.mdpi.com/journal/molecules

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