Anti-cancer agents delivered to cancer cells often show multi-drug resistance (MDR) due to expulsion of the agents. One way to address this problem is to increase the accumulation of anti-cancer agents in cells via amino acid transporters. Thus, val-lapatinib and tyr-lapatinib were newly synthesized by adding valine and tyrosine moieties, respectively, to the parent anti-cancer agent lapatinib without stability issues in rat plasma. Val-lapatinib and tyr-lapatinib showed enhanced anti-cancer effects versus the parent lapatinib in various cancer cell lines, including human breast cancer cells (MDA-MB-231, MCF7) and lung cancer cells (A549), but not in non-cancerous MDCK-II cells. A glutamine uptake study revealed that both val-lapatinib and tyr-lapatinib, but not the parent lapatinib, inhibited glutamine transport in MDA-MB-231 and MCF7 cells, suggesting the involvement of amino acid transporters. In conclusion, val-lapatinib and tyr-lapatinib have enhanced anti-cancer effects, likely due to an increased uptake of the agents into cancer cells via amino acid transporters. The present data suggest that amino acid transporters may be an effective drug delivery target to increase the uptake of anti-cancer agents, leading to one method of overcoming MDR in cancer cells.

Here we report the discovery of a series of potent hepatitis C virus (HCV) NS5A inhibitors based on the benzidine prolinamide backbone. Taking a simple synthetic route, we developed a novel inhibitor structure, which allows easy modification, and through optimization of the capping group, we identified compound 6 with highly potent anti-HCV activity. Compound 6 is nontoxic and is anticipated to be an effective HCV drug candidate.

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Based on ()--methyl--(5-azaspiro[2.4]heptan-7-yl)-7-pyrrolo[2,3-]pyrimidin-4-amine as a core scaffold, we identified ()-3-(7-(methyl(7-pyrrolo[2,3-]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile [-] as a JAK1 selective inhibitor. The structural design was based on the combination of tofacitinib's 7-deazapurine and 5-azaspiro[2.4]heptan-7-amine. Compound - exhibited an IC value of 8.5 nM against JAK1 with a selectivity index of 48 over JAK2. To optimize - as a lead compound, we performed ADME, hERG, kinase profiling, and pharmacokinetic tests. Mouse and rat studies verified that - exhibited desired efficacies in CIA and AIA models.