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DPS-2: A Novel Dual MEK/ERK and PI3K/AKT Pathway Inhibitor with Powerful Ex Vivo and In Vivo Anticancer Properties.

Abstract：

:Development of novel bioactive compounds against KRAS and/or BRAF mutant colorectal cancer (CRC) is currently an urgent need in oncology. In addition, single or multitarget kinase inhibitors against MEK/ERK and PI3K/AKT pathways are of potential therapeutic advantage. A new compound based on the benzothiophene nucleus was synthesized, based on previous important outcomes on other pharmaceutical preparations, to be tested as potential anticancer agent. Treatments by 2-5 μM DPS-2 of several CRC and melanoma cell lines bearing either BRAF or KRAS mutations have shown a remarkable effect on cell viability in 2D and 3D cultures. More detailed analysis has shown that DPS-2 can kill cancer cells by apoptosis, reducing at the same time their autophagy properties. After testing activities of several signaling pathways, the compound was found to have a dual inhibition of two major proliferative/survival pathways, MEK/ERK and PI3K/AKT, in both CRC and melanoma, thus providing a mechanistic evidence for its potent anticancer activity. Antitumor activity of DPS-2 was further validated in vivo, as DPS-2 treatment of mouse xenografts of Colo-205 colorectal cancer cells remarkably reduced their tumor formation properties. Our findings suggest that DPS-2 has significant anti-KRAS/ anti-BRAF mutant CRC activity in preclinical models, potentially providing a novel treatment strategy for these difficult-to-treat tumors, which needs to be further exploited.

journal_name

Transl Oncol

journal_title

Translational oncology

authors

Goulielmaki M,Assimomytis N,Rozanc J,Taki E,Christodoulou I,Alexopoulos LG,Zoumpourlis V,Pintzas A,Papahatjis D

doi

10.1016/j.tranon.2019.04.005

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

932-950

issue

7

issn

1936-5233

pii

S1936-5233(19)30013-0

journal_volume

12

pub_type

杂志文章

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