Novel Adamantanyl-Based Thiadiazolyl Pyrazoles Targeting EGFR in Triple-Negative Breast Cancer

ACS Omega
Anusha SebastianKanchugarakoppal S Rangappa

Abstract

The epidermal growth factor receptor (EGFR) is a validated therapeutic target for triple-negative breast cancer (TNBC). In the present study, we synthesize novel adamantanyl-based thiadiazolyl pyrazoles by introducing the adamantane ring to thiazolopyrazoline. On the basis of loss of cell viability in TNBC cells, 4-(adamantan-1-yl)-2-(3-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazole (APP) was identified as a lead compound. Using a Parzen-Rosenblatt Window classifier, APP was predicted to target the EGFR protein, and the same was confirmed by surface plasmon resonance. Further analysis revealed that APP suppressed the phosphorylation of EGFR at Y992, Y1045, Y1068, Y1086, Y1148, and Y1173 in TNBC cells. APP also inhibited the phosphorylation of ERK at Y204 and of STAT3 at Y705, implying that APP downregulates the activity of EGFR downstream effectors. Small interfering RNA mediated depletion of EGFR expression prevented the effect of APP in BT549 and MDA-MB-231 cells, indicating that APP specifically targets the EGFR. Furthermore, APP modulated the expression of the proteins involved in cell proliferation and survival. In addition, APP altered the expression of epithelial-mesenchymal transition related protein...Continue Reading

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Citations

Mar 24, 2020·Organic & Biomolecular Chemistry·Sadashivamurthy ShamanthKempegowda Mantelingu
May 15, 2018·Frontiers in Pharmacology·Fazilath UzmaElsayed F Abd Allah
Jul 10, 2019·Chemistry & Biodiversity·Kanchugarakoppa RangappaRakesh Bhatnagar
Oct 13, 2018·Proceedings of the National Academy of Sciences of the United States of America·Vijay PandeyPeter E Lobie
Sep 25, 2020·Biomedicines·Vikas H MalojiraoKanchugarakoppal S Rangappa
Apr 5, 2018·Frontiers in Oncology·Chakrabhavi Dhananjaya MohanKanchugarakoppal S Rangappa
Apr 24, 2020·Seminars in Cancer Biology·Chakrabhavi Dhananjaya MohanKanchugarakoppal S Rangappa
Sep 2, 2017·Analytical Chemistry·Congcong ShenAvraham Rasooly

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Methods Mentioned

BETA
flow cytometry
confocal microscopy
surface plasmon resonance
chip
electrophoresis
transfection
NMR
fluorescence microscopy

Software Mentioned

GraphPad Prism5
ChEMBL
BIA
GraphPad Prism
BIACORE

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