Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer

Abstract Hedgehog (Hh) pathway is involved in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) maintenance resulting in tumor progression. GDC-0449, an inhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cancers including pancreatic canc...

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Autores principales:	Vinod Kumar, Amit Kumar Chaudhary, Yuxiang Dong, Haizhen A. Zhong, Goutam Mondal, Feng Lin, Virender Kumar, Ram I. Mahato
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc04897ea06a4b9b92226e9887c43bf1
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spelling	oai:doaj.org-article:bc04897ea06a4b9b92226e9887c43bf12021-12-02T16:07:47ZDesign, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer10.1038/s41598-017-01942-72045-2322https://doaj.org/article/bc04897ea06a4b9b92226e9887c43bf12017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01942-7https://doaj.org/toc/2045-2322Abstract Hedgehog (Hh) pathway is involved in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) maintenance resulting in tumor progression. GDC-0449, an inhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cancers including pancreatic cancer. However, the emergence of resistance during GDC-0449 treatment with numerous side effects limits its use. Therefore, here we report the design, synthesis and evaluation of novel GDC-0449 analogs using N-[3-(2-pyridinyl) phenyl] benzamide scaffold. Cell-based screening followed by molecular simulation revealed 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4-bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) as most potent analog, binding with an extra interactions in seven-transmembrane (7-TM) domain of Smo due to an additional 2-pyridylmethyl group than GDC-0449. Moreover, MDB5 was more efficient in inhibiting Hh pathway components as measured by Gli-1 and Shh at transcriptional and translational levels. Additionally, a significant reduction of ALDH1, CD44 and Oct-3/4, key markers of pancreatic CSC was observed when MIA PaCa-2 cells were treated with MDB5 compared to GDC-0449. In a pancreatic tumor mouse model, MDB5 containing nanoparticles treated group showed significant inhibition of tumor growth without loss in body weight. These evidence highlight the enhanced Hh pathway inhibition and anticancer properties of MDB5 leaving a platform for mono and/or combination therapy.Vinod KumarAmit Kumar ChaudharyYuxiang DongHaizhen A. ZhongGoutam MondalFeng LinVirender KumarRam I. MahatoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vinod Kumar Amit Kumar Chaudhary Yuxiang Dong Haizhen A. Zhong Goutam Mondal Feng Lin Virender Kumar Ram I. Mahato Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
description	Abstract Hedgehog (Hh) pathway is involved in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) maintenance resulting in tumor progression. GDC-0449, an inhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cancers including pancreatic cancer. However, the emergence of resistance during GDC-0449 treatment with numerous side effects limits its use. Therefore, here we report the design, synthesis and evaluation of novel GDC-0449 analogs using N-[3-(2-pyridinyl) phenyl] benzamide scaffold. Cell-based screening followed by molecular simulation revealed 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4-bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) as most potent analog, binding with an extra interactions in seven-transmembrane (7-TM) domain of Smo due to an additional 2-pyridylmethyl group than GDC-0449. Moreover, MDB5 was more efficient in inhibiting Hh pathway components as measured by Gli-1 and Shh at transcriptional and translational levels. Additionally, a significant reduction of ALDH1, CD44 and Oct-3/4, key markers of pancreatic CSC was observed when MIA PaCa-2 cells were treated with MDB5 compared to GDC-0449. In a pancreatic tumor mouse model, MDB5 containing nanoparticles treated group showed significant inhibition of tumor growth without loss in body weight. These evidence highlight the enhanced Hh pathway inhibition and anticancer properties of MDB5 leaving a platform for mono and/or combination therapy.
format	article
author	Vinod Kumar Amit Kumar Chaudhary Yuxiang Dong Haizhen A. Zhong Goutam Mondal Feng Lin Virender Kumar Ram I. Mahato
author_facet	Vinod Kumar Amit Kumar Chaudhary Yuxiang Dong Haizhen A. Zhong Goutam Mondal Feng Lin Virender Kumar Ram I. Mahato
author_sort	Vinod Kumar
title	Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
title_short	Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
title_full	Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
title_fullStr	Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
title_full_unstemmed	Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
title_sort	design, synthesis and biological evaluation of novel hedgehog inhibitors for treating pancreatic cancer
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bc04897ea06a4b9b92226e9887c43bf1
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_version_	1718384741058609152

Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer

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