Novel adamantanyl-based thiadiazolyl pyrazoles targeting EGFR intriple-negative Breast Cancer

Anusha, Sebastian and Pandey, Vijay and Mohan, C. D. and Chia, Yi Ting and Shobith, R. and Mathai, Jessin and Baburajeev, C. P. and Paricharak, S. and Mervin, Lewis H. and Bulusu, K. C. and Fuchs, J. E. and Bender, A. and Yamada, Shuhei and Basappa and Lobie, P. E. and Rangappa, K. S. (2016) Novel adamantanyl-based thiadiazolyl pyrazoles targeting EGFR intriple-negative Breast Cancer. ACS Omega, 1 (6). pp. 1412-1424.

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The epidermal growth factor receptor (EGFR) is avalidated therapeutic target for triple-negative breast cancer (TNBC).In the present study, we synthesize novel adamantanyl-basedthiadiazolyl pyrazoles by introducing the adamantane ring tothiazolopyrazoline. On the basis of loss of cell viability in TNBCcells, 4-(adamantan-1-yl)-2-(3-(2,4-dichlorophenyl)-5-phenyl-4,5-dihy-dro-1H-pyrazol-1-yl)thiazole (APP) was identified as a lead compound.Using a Parzen−Rosenblatt Window classifier, APP was predicted totarget the EGFR protein, and the same was confirmed by surfaceplasmon resonance. Further analysis revealed that APP suppressed thephosphorylation of EGFR at Y992, Y1045, Y1068, Y1086, Y1148, andY1173 in TNBC cells. APP also inhibited the phosphorylation of ERKat Y204 and of STAT3 at Y705, implying that APP downregulates theactivity of EGFR downstream effectors. Small interfering RNAmediated depletion of EGFR expression prevented the effect of APP in BT549 and MDA-MB-231 cells, indicating that APPspecifically targets the EGFR. Furthermore, APP modulated the expression of the proteins involved in cell proliferation andsurvival. In addition, APP altered the expression of epithelial− mesenchymal transition related proteins and suppressed theinvasion of TNBC cells. Hence, we report a novel and specific inhibitor of the EGFR signaling cascade.

Item Type: Article
Subjects: C Chemical Science > Chemistry
Divisions: Department of > Chemistry
Depositing User: Manjula P Library Assistant
Date Deposited: 18 Jun 2019 06:09
Last Modified: 04 Jul 2019 10:16

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