NOVEL INHIBITORS OF GLUCOSE TRANSPORTER 1 FOR CANCER
GLUT1 transports glucose across the cell membrane, plays an important role during several stages of cancer progression, and is essential to the survival of many types of cancer. After reviewing existing docking research on the 4 known inhibitors of GLUT1, 23 docking positions were determined and then tested in 10 trials. The best docking position identified was then used for a High Throughput Molecular Docking Study of 47 million ligands with GLUT1. Thousands of ligands found had much more effective docking results than the 4 existing drugs. Top novel-inhibitor candidates (40%-63% improvement in binding free energy compared to existing inhibitors) were chosen after toxicity-testing and 5 trials of tests with 7 optimal-docking positions.
BJD000029 and BJD000021 are two great examples of new ligands designed through structural manipulation. The methodology used in this experiment streamlined the hit to lead process.
An important discovery of this experiment is Merck Pharmaceuticals’ Akt inhibitor MK-2206’s potential as a GLUT1 inhibitor. It had lower Gibbs free energy than any existing GLUT1 inhibitor. Currently, it’s in phase II of clinical trials.
Based on 10 trials of tests and evaluation of toxicity, lipophilicity, solubility, a top 10 list of novel candidate-inhibitors was created. Among them, ZINC08918302, ZINC16847726 and MK-2206 were selected for testing in cancer cell cultures. One great advantage of the top novel candidate-inhibitors is that they all successfully passed the toxicity check, unlike the existing inhibitors.