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HER2 overexpression induces cancer aggression and frequent recurrences in many solid tumors. Because HER2 overproduction is generally followed by gene amplification, inhibition of protein-protein interaction (PPI) between transcriptional factor ELF3 and its coactivator MED23 has been considered an effective but challenging strategy.This study aimed to determine the hotspot of ELF3-MED23 PPI and further specify the essential residues and their key interactions in the hotspot which are controllable by small molecules with significant anticancer activity.Intensive biological evaluation methods including SEAP, fluorescence polarization, LC-MS/MS-based quantitative, biosensor, GST-pull down assays, and in silico structural analysis were performed to determine hotspot of ELF3-MED23 PPI and to elicit YK1, a novel small molecule PPI inhibitor. The effects of YK1 on possible PPIs of MED23 and the efficacy of trastuzumab were assessed using cell culture and tumor xenograft mouse models.ELF3-MED23 PPI was found to be specifically dependent on H-bondings between D400, H449 of MED23 and W138, I140 of ELF3 for upregulating HER2 gene transcription. Employing YK1, we confirmed that interruption on these H-bondings significantly attenuated the HER2-mediated oncogenic signaling cascades and exhibited significant in vitro and in vivo anticancer activity against HER2-overexpressing breast and gastric cancers even in their trastuzumab refractory clones.Our approach to develop specific ELF3-MED23 PPI inhibitor without interfering other PPIs of MED23 can finally lead to successful development of a drug resistance-free compound to interrogate HER2 biology in diverse conditions of cancers overexpressing HER2.

Fluorescein hydrazones ( 5 and 7 ) were synthesized in three/four steps with 82–92% yields. All synthesized compounds were evaluated by topoisomerase I (topo I) and topoisomerase IIα (topo IIα)-mediated relaxation and cell viability assays. Among them, most of the compounds showed topo I & IIα inhibitory activity and nineteen compounds showed strong anti-proliferative activity against various cell lines. In brief, 5e inhibited 53% topo IIα (etoposide 29%) at 20 μ M and showed excellent antiproliferative activity against DU145 (1.43 ± 0.04 μM), HCT15 (2.4 ± 0.03 μM) and MCF7 (11.4 ± 0.5 μM) cell lines in comparison with adriamycin, etoposide, and camptothecin. Compounds 5e , 5g and 5h were further evaluated to determine their mode of action. Compounds 5e , 5g and 5h functioned as non-intercalative topo IIα catalytic inhibitor with induction of G1 arrest and activation of apoptotic proteins in dose-dependent manner.

With the aim to develop novel antiproliferative agents, a new series of eighteen dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were systematically designed, prepared, and investigated for their topoisomerase (topo) I and IIα inhibitory properties and antiproliferative effect in three different human cancer cell lines (HCT15, T47D, and HeLa). Compounds 22-30 which possess a meta- or para-phenol on 2-, or 6-position of central pyridine ring showed significant dual topo I and topo IIα inhibitory activities with strong antiproliferative activities against all the tested human cancer cell lines. However, compounds 13-21 which possess an ortho-phenol on 2-, or 6-position of central pyridine ring did not show significant topo I and topo IIα inhibitory activities but displayed moderate antiproliferative activities against all the tested human cancer cell lines. Compound 23 exhibited the highest antiproliferative potency as much as 348.5 and 105 times compared to etoposide and camptothecin, respectively, in T47D cancer cell line. The structure-activity relationship study revealed that the para position of a hydroxyl group at 2-and 6-phenyl ring and chlorine atom at the para position of 4-phenyl ring of the central pyridine exhibited the most significant topo I and topo IIα inhibition, which might indicate introduction of the chlorine atom at the phenyl ring of 4-pyridine have an important role as dual inhibitors of topo I and topo IIα. Compound 30 which showed the most potent dual topo I and topo IIα inhibition with strong antiproliferative activity in T47D cell line was selected to perform further study on the mechanism of action, which revealed that compound 30 functions as a potent DNA non-intercalative catalytic topo I and IIα dual inhibitor.

As a part of ongoing studies in developing novel anticancer agents, a series of modified 2,4-diaryl-5H-indeno[1,2-b]pyridines were designed, and synthesized by introducing hydroxyl and chlorine moieties. They were evaluated for topoisomerase inhibitory activity and cytotoxicity against HCT15, T47D, and HeLa cancer cell lines. This modification allowed us to demonstrate structure-activity relationship (SAR) study with respect to the non-substituted 2,4-diaryl-5H-indeno[1,2-b]pyridines. Compounds (2, 3, 4, 5, 8, and 9) with meta or para hydroxyl group on 2 or 4-phenyl ring have enhanced topo I and II inhibitory activity and cytotoxicity. However, additional substitution of chlorine group on furyl or thienyl ring (11, 12, 14, 16-18) generally reduced topo I and II inhibitory activity but improved cytotoxicity. The observation of cytotoxic properties and SAR study according to the position of hydroxyl and chlorine group will provide valuable insight for further study of development of novel anticancer agents with related scaffolds.

A new series of thirty-six dihydroxylated 2,6-diphenyl-4-aryl pyridines containing hydroxyl groups at the ortho, meta, or para position of 2- and 6-phenyl rings attached to the central pyridine were designed and synthesized. They were evaluated for topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with hydroxyl moiety either at the meta or para position of 2- or 6-phenyl ring in combination with thienyl or furyl group at 4-position of central pyridine displayed significant topoisomerase II inhibitory activity and cytotoxicity. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the compounds 9-11, 15-17, 19, 21-23, 28, and 41. Among all the synthesized compounds, compound 17 emerged as the most promising topoisomerase II inhibitor with significant cytotoxicity.