TY - JOUR
T1 - Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer
AU - Kumar, Vinod
AU - Chaudhary, Amit Kumar
AU - Dong, Yuxiang
AU - Zhong, Haizhen A.
AU - Mondal, Goutam
AU - Lin, Feng
AU - Kumar, Virender
AU - Mahato, Ram I.
N1 - Funding Information:
We gratefully acknowledge the financial support by the National Institutes of Health (1R01 GM113166), the Fred and Pamela Buffet Cancer Center, and a Faculty Start-up fund to R.I.M.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-017-01942-7
DO - 10.1038/s41598-017-01942-7
M3 - Article
C2 - 28490735
AN - SCOPUS:85019182434
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 1665
ER -