Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Abstract

3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their potential to inhibit tumor growth in vivo, the human HT-29 tumor xenograft model was used. Moguntinones prominently inhibit several protein kinases associated with tumor growth and metastasis. Specific signaling pathways such as GSK3b and mTOR downstream targets were inhibited with IC 50 values in the nanomolar range. GSK3b signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 mmol/L, MOG-19 in combination with topoisomerase I inhibitors induced apoptosis synergistically at lower concentrations. Consistent with in vitro data, MOG-19 significantly reduced tumor volume and weight in combination with a topoisomerase I inhibitor in vivo. Our in vitro and in vivo data present significant proapoptotic, antiangiogenic, and antiproliferative effects of MOG-19 in different human colon cancer cells. Combination with clinically relevant topoisomerase I inhibitors in vitro and xenograft mouse model demonstrate a high potency of moguntinones to complement and improve standard chemotherapy options in human colorectal cancer. Mol Cancer Ther; 13(6); 1399-409. Ó2014 AACR.

Novel Siglec-15-Sia axis inhibitor leads to colorectal cancer cell death by targeting miR-6715b-3p and oncogenes

“…Similarly, a previous study highlighted Actein, a triterpene glycoside, significantly inhibited SW480 and HT-29 cells in vitro whilst exhibiting reduced anti-proliferation effects in HCoEPiC cells (49). Furthermore, MOG13 a selective inhibitor for CRC treatment, witnessed a concentrationdependant reduction in cellular viability when exposed to drug treatment (50). This could suggest that significantly higher concentrations from 40mM onwards could sensitise HCoEPiC cells towards SHG-8 treatment.…”

The Azaindole Framework in the Design of Kinase Inhibitors

“…The azaindole nitrogen, being only about 3.6 from the carboxyl group of Asp200 may form an additional H-bond [7]. Bisarylmaleimides, also known as moguntinones have been very recently described as new selective inhibitors for the treatment of human colorectal cancer [136].…”

Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates

“…Recent work on analogous derivatives by Dannhardt et al, such as maleimides 11 and 12 containing 7-azaindolyl and 6-azaindolyl functionalities, respectively, has illustrated potent inhibition of angiogenesis and cell proliferation ( Figure 4 ) [ 24 , 25 ]. In examining the molecular targets associated with the candidates 11 and 12 , significant activity was observed for both against VEGFR-2 and FLT-3 protein kinases.…”

“…Furthermore, it was found that although 6-azaindolyl 12 was a potent inhibitor of GSK-3β, 7-azaindolyl 11 is completely inactive against the same enzyme. In addition, this group has described selective treatment of colorectal cancer using this template [ 24 , 25 ].…”