Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2015 Sep 1;25(17):3665-70. doi: 10.1016/j.bmcl.2015.06.049. Epub 2015 Jun 18.

Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors.

Author information

1
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
2
BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
3
BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China. Electronic address: lusong.luo@beigene.com.
4
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China. Electronic address: xiaohuzhang@suda.edu.cn.

Abstract

Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization.

KEYWORDS:

Cancer therapy; GPCR; Hedgehog pathway; Kinase; PI3K/AKT/mTOR pathway; Polypharmacology

PMID:
26119500
DOI:
10.1016/j.bmcl.2015.06.049
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center