HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated potent and selective inhibitions (IC 50 : 5.4−12 nM) compared to lapatinib (IC 50 : 95.5 nM). Favorably, 17d exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI 50 : 1.43−2.09 μM) and 17d had a remarkable selectivity toward BC. Our compounds revealed significant selective and potent antiproliferative activities (∼20-fold) against HER2+ (AU565, BT474) compared to HER2(−) cells. At 0.1 IC 50 , 15i, 17d, and 25b inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, 17d demonstrated potent in vivo tumor regression against the BT474 xenograft model. Notably, a metastasis case was observed in the vehicle but not in the test mice groups. CD-1 mice metabolic stability assay revealed high stability and low intrinsic clearance of 17d (T 1/2 > 145 min and CL int(mic) < 9.6 mL/min/kg).

No abstract

Novel 5-deazaflavins were designed as potential anticancer candidates. Compounds 4j, 4k, 5b, 5i, and 9f demonstrated high cytotoxicity against MCF-7 cell line with IC 50 of 0.5–190nM. Compounds 8c and 9g showed preferential activity against Hela cells (IC 50 : 1.69 and 1.52 μM respectively). However, compound 5d showed notable potency against MCF-7 and Hela cell lines of 0.1 nM and 1.26 μM respectively. Kinase profiling for 4e showed the highest inhibition against a 20 kinase panel. Additionally, ADME prediction studies exhibited that compounds 4j , 5d, 5f, and 9f have drug-likeness criteria to be considered promising antitumor agents deserving of further investigation. SAR study showed that substitutions with 2-benzylidene hydra zino have a better fitting into PTK with enhanced antiproliferative potency. Noteworthy, the incorporation of hydrazino or ethanolamine moieties at position 2 along with small alkyl or phenyl at N-10, respectively revealed an extraordinary potency against MCF-7 cells with IC 50 values in the nanomolar range.