121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-633
Subject Synergistic Anti-Cancer Effect of Vandetanib (RTK-inbibitor) and an SHP2 inhibitor towards T cell-Acute Lymphoblastic Leukemia (T-ALL)
Authors Se Jeong Kwon, hyo jin kang1,*, Sang Jeon Chung2,*
pharmacy, Sungkyunkwan University, Korea
1Department of Chemistry, Dongguk University, Korea
2Department of Chemistry, SungKyunKwan University, Korea
Abstract FDA -approved vandetanib is a small-molecule receptor tyrosine kinase (RTK) inhibitor that is used in cancer treatment. However, resistance to vandetanib can be developed within a few years, resulting in cancer relapse. SHP2 is a key enzyme in the RAS/ERK signaling pathway associated with RTK and Ras proteins and is a key mediator of programmed cell death 1 and B- and T-lymphocyte attenuator immune checkpoint pathways. Based on the involvement of SHP2 and RTK in cell proliferation, we hypothesized that simultaneous inhibition of SHP2 and RTK could result in a potent anticancer effect overcoming cellular resistance to vandetanib. However, the majority of SHP2 inhibitors suffer from poor selectivity as they also target various other protein tyrosine phosphatases (PTPs), presumably due to the highly conserved active site of PTPs. To search SHP2 inhibitors, we screened 658 phytochemicals to identify many natural product SHP2 inhibitors with strong inhibitory activity, however only polyphyllin D and demethylzeylasteral showed inhibitory selectivity to SHP2 over other PTPs although their inhibitory activities are moderate. Furthermore, T-cell acute lymphoblastic leukemia cell lines were treated with vandetanib and the selected SHP2 inhibitors. Combination index values were determined to demonstrate that vandetanib and SHP2 inhibitor show synergistic inhibition of cancer cell growth. Increase in PARP cleavage and caspase-3 activation was observed, meaning that the combination of vandetanib and SHP2 inhibitors induce stronger cancer cell apoptosis compared to vandetanib or SHP2 inhibitor only.
E-mail sejung1110@naver.com