Jung Ae Kim

Synthesis, topoisomerase I inhibition and antitumor cytotoxicity of 2,2':6',2"-, 2,2':6',3"- and 2,2':6',4"-terpyridine derivatives.

For the development of new anticancer agents, 2,2:6,2-, 2,2:6,3- and 2,2:6,4-terpyridine derivatives were designed and evaluated for their topoisomerase I inhibitory activity and antitumor cytotoxicity. Structure-activity relationship studies indicated that 2,2:6,2-terpyridine derivatives were highly cytotoxic toward several human tumor cell lines, whereas 2,2:6,3- and 2,2:6,4-terpyridine derivatives were potent topoisomerase I inhibitors.

NADPH oxidase inhibitors: a patent review.

Introduction: NADPH oxidases, a family of multi-subunit enzyme complexes, catalyze the production of reactive oxygen species (ROS), which may contribute to the pathogenesis of a variety of diseases. In addition to the first NADPH oxidase found in phagocytes, four non-phagocytic NADPH oxidase isoforms have been identified, which all differ in their catalytic subunit (Nox1-5) and tissue distribution. Areas covered: This paper provides a comprehensive review of the patent literature on NADPH oxidase inhibitors, small molecule Nox inhibitors, peptides and siRNAs. Expert opinion: Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility.

Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling

BackgroundTriple-negative breast cancer (TNBC) has a high risk of relapse and there are few chemotherapy options. Although 5-hydroxytryptamine (5-HT, serotonin) signaling pathways have been suggested as potential targets for anti-cancer drug development, the mechanism responsible for the action of 5-HT in TNBC remains unknown.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. Cell proliferation was measured using CellTiter 96 Aqueous One Solution. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Levels of 5-HT and vascular endothelial growth factor (VEGF) were measured using ELISA kits. Chick chorioallantoic membrane (CAM) assay and mouse tumor model were used to investigate the in vivo effects of SB269970, a 5-HT7 receptor antagonist, and BJ-1113, a novel synthetic compound.ResultsTNBC cell lines (MDA-MB-231, HCC-1395, and Hs578T) expressed higher levels of tryptophan hydroxylase 1 (TPH1) than hormone-responsive breast cancer cell lines (MCF-7 and T47D). In MDA-MB-231 cells, 5-HT promoted invasion and proliferation via 5-HT7 receptor, and interestingly, the stimulatory effect of 5-HT on MDA-MB-231 cell invasion was stronger than its effect on proliferation. Likewise, downstream signaling pathways of 5-HT7 differed during invasion and proliferation, that is, Gα-activated cAMP and Gβγ-activated kinase signaling during invasion, and Gβγ-activated PI3K/Akt signaling during proliferation. Also, 5-HT increased the protein expressions of TPH1 and VEGF in MDA-MB-231 cells. These results provide insight of the stimulatory effect of 5-HT on breast cancer progression; 5-HT was found to act more strongly during the first stage of metastasis (during invasion and migration) than during the later proliferative phase after local invasion. Interestingly, these actions of 5-HT were inhibited by BJ-1113, a 6-amino-2,4,5-trimethylpyridin-3-ol analog. BJ-1113 blocked intracellular signaling pathways initiated by 5-HT7 receptor activation, and exhibited anti-proliferative and anti-invasive activities against MDA-MB-231 cells. Furthermore, the inhibitory effect of BJ-1113 against MDA-MB-231 tumor growth was greater than that of SB269970, a 5-HT7 receptor antagonist.Conclusions5-HT7 receptor which mediates 5-HT-induced cancer progression is a potential therapeutic target in TNBC, and BJ-1113 offers a novel scaffold for the development of anti-cancer agents against TNBC.

Dual inhibition of NOX2 and receptor tyrosine kinase by BJ-1301 enhances anticancer therapy efficacy via suppression of autocrine-stimulatory factors in lung cancer

NADPH oxidase–derived reactive oxygen species (ROS) potentiate receptor tyrosine kinase (RTK) signaling, resulting in enhanced angiogenesis and tumor growth. In this study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g., ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 inhibited cisplatin-resistant lung cancer cell proliferation more than sunitinib did. In xenograft chick or mouse tumor models, BJ-1301 inhibited lung tumor growth, to an extent greater than that of sunitinib or cisplatin. Treatments with BJ-1301 induced regression of tumor growth, potentially due to downregulation of autocrine-stimulatory ligands for RTKs, such as TGFα and stem cell factor, in tumor tissues. Taken together, the current study demonstrates that BJ-1301 is a promising anticancer drug for the treatment of lung cancer. Mol Cancer Ther; 16(10); 2144–56. ©2017 AACR.