Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment.

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.

Discovery of thiazole salt AChE inhibitors and development of thiamine disulfide prodrugs targeting the central nervous system.

The selective AChE inhibitor donepezil has been approved by the FDA as a first-line drug for the treatment of mild to moderate AD. However, many peripheral side effects were observed in patients taking donepezil. Our main objective here is to provide insight into the opportunities and challenges associated with development of AChE inhibitors with high brain exposure and low peripheral side effects. In this study, we have for the first time revealed a series of novel thiazole salt AChE inhibitors, which exhibit a nanomolar inhibitory effect on human AChE. We further developed thiamine disulfide prodrugs based on optimized thiazole salt AChE inhibitors, which are reduced in the brain to form thiazole salt AChE inhibitors. In vivo experiments have confirmed that the representative prodrug Tap4 (i.p., 10 mg/kg) can be converted into the thiazole salt AChE inhibitor Tat2 and shows high brain exposure, reaching 500 ng/g. Further, the inhibitory effect of the prodrug Tap4 on AChE is obviously stronger in the brain than that on intestinal AChE of ICR mice. Our study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.

Discovery of 2-(cyclopropanecarboxamido)-N-(5-((1-(4-fluorobenzyl)piperidin-4-yl)methoxy)pyridin-3-yl)isonicotinamide as a potent dual AChE/GSK3ß inhibitor for the treatment of Alzheimer's disease: Significantly increasing the level of acetylcholine in the brain without affecting that in intestine.

Acetylcholinesterase (AChE) inhibitors are currently the first-line drugs approved by the FDA for the treatment of Alzheimer's disease (AD). However, a short effective-window limits their therapeutic benefits. Clinical studies have confirmed that the combination of AChE inhibitors and neuroprotective agents exhibits better anti-AD effects. We have previously reported that the dual AChE/GSK3ß (Glycogen synthase kinase 3ß) modulators have both neuroprotective effects and cognitive impairment-improvement effects. In this study, we characterized a new backbone of the AChE/GSK3ß inhibitor 11c. It was identified as a highly potent AChE inhibitor and was found superior to donepezil, the first-line drug for the treatment of AD. In vivo studies confirmed that 11c significantly inhibited the activity of AChE in the brain but had little effect on the activity of AChE in the intestine. This advantage of 11c was expected to reduce the peripheral side effects caused by donepezil. Furthermore, biomarker studies have shown that 11c also improved the levels of acetylcholine and synaptophysin in the brain and exhibited neuroprotective effects. Preliminary in vivo and in vitro research results underline the exciting potential of compound 11c in the treatment of AD.