Year 3

During the reporting period, we have made significant progress toward discovering new molecules and conditions that can induce the generation of the earlier developmental, naïve state of pluripotency in human cells. Specifically, we have carried out additional high throughput screening of chemical libraries for enhancing conversion of conventional human embryonic stem cells to the earlier developmental, naive pluripotency state. Novel hit compounds were identified from the screen, and validated. To further improve and characterize the molecules, we established the synthetic chemistry to generate analogs of one compound series, have conducted structure-activity-relationship study, and found activity improved compounds. This also allowed generation of affinity chromatography probes for target identification. Furthermore, mechanistic studies suggested two distinct pathways that affect the conversion to naïve state.