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

Vinod Kumar, Amit Kumar Chaudhary, Yuxiang Dong, Haizhen Andrew Zhong, Goutam Mondal, Feng Lin, Virender Kumar, Ram I Mahato

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number1665
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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HhAntag691
Hedgehogs
Pancreatic Neoplasms
Neoplastic Stem Cells
Neoplasms
Epithelial-Mesenchymal Transition
Mesenchymal Stromal Cells
Nanoparticles
Body Weight
Maintenance
Growth

ASJC Scopus subject areas

  • General

Cite this

Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer. / Kumar, Vinod; Chaudhary, Amit Kumar; Dong, Yuxiang; Zhong, Haizhen Andrew; Mondal, Goutam; Lin, Feng; Kumar, Virender; Mahato, Ram I.

In: Scientific Reports, Vol. 7, No. 1, 1665, 01.12.2017.

Research output: Contribution to journalArticle

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