Discovery of novel hydroxyamidine based indoleamine 2,3-dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) dual inhibitors.

In order to take advantage of both immunotherapeutic and metabolic antitumor agents, novel dual indoleamine 2,3- dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) inhibitors were designed. Thioredoxin reductase 1 (TrxR1) is a main ROS modulator within CRC cells. Indoleamine 2,3-dioxygenase (IDO1) is crucial controller for tryptophan (Trp) metabolism that is also important for CRC immunotherapy. Herein, ten compounds 12a-j containing hydroxyamidine scaffold were designed, synthesized and evaluated for inhibitory activities against IDO1/TrxR1 enzyme and CRC cells. Among these compounds, the most active compound 12d (ZC0109) showed excellent and balanced activity against both IDO1 (IC50 = 0.05 µM) and TrxR1 (IC50 = 3.00 ± 0.25 µM) were selected for further evaluation. Compound ZC0109 exhibited good dual inhibition against IDO1 and TrxR1 both in vitro and in vivo. Further mechanistic studies reveal that, through IDO1 and TrxR1 inhibition by ZC0109 treatment, accumulated ROS effectively induced apoptosis and G1/S cell cycle arrest in cancer cells. In vivo evaluation demonstrated excellent anti-tumor effect of ZC0109 with the notable ability of promoting ROS-induced apoptosis, reducing kynurenine level in plasma and restoring anti-tumor immune response. Thus, ZC0109 represents a potential CRC therapy agent for further development.

Distance-construal relationship: Mediating role of perceived control and moderating role of locus of control.

The construal level theory (CLT) has been supported and applied widely in social psychology. Yet, what remains unclear is the mechanism behind it. The authors extend the current literature by hypothesizing that perceived control mediates and locus of control (LOC) moderates the effect of psychological distance on the construal level. Four experimental studies were conducted. The results indicate that individuals perceive low (vs. high) situational control from a psychological distance (vs. proximity), and the resultant control perception influences their motivation in control pursuit, producing a high (vs. low) construal level. Moreover, LOC (i.e., one's chronic control belief) affects an individual's motivation to pursue control and yields a reversal of distance-construal relationship under external (vs. internal) LOC as a result. Overall, this research first identifies perceived control as a closer predictor of construal level, and the findings are expected to help with influencing human behavior by facilitating individuals' construal level via control-related constructs.