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Identification, characterization and optimization of chemicals for the generation of human chemically induced pluripotent stem cells

Applicant Dr. Xinlai Cheng
Subject Area Pharmacy
Biochemistry
Term from 2016 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 321028751
 
Final Report Year 2024

Final Report Abstract

In the field of chemically induced human pluripotent stem cell (iPSC) generation, the primary objective of this project was to identify and develop small molecules capable of replacing reprogramming-associated transcription factors, specifically focusing on OCT4, a master transcription factor crucial for reprogramming. During the initial phase (2016-2019), our focus was on OCT4, leading to the successful validation of three OCT4-inducing compounds: O4I1, O4I2, and O4I3. Through comprehensive biochemical and cell biology assays, we discovered that O4I3, an imidazopyridine compound, functions as a novel H3K4-specific demethylase (KDM5) inhibitor. This inhibition of H3K4 demethylation resulted in enhanced occupation of H3K4Me3 at the OCT4 promoter, significantly increasing reprogramming efficiency in primary fibroblasts. Notably, these innovative compounds were patented in collaboration with the University of Heidelberg. The second phase of the project (2020-2023) focused on evaluating whether lead structures or their derivatives could replace OCT4 in the presence of other reprogramming-associated transcription factors, namely SOX2, KLF4, MYC, and LIN28 (SKML). Our observation of a transient activation of OCT4 in the presence of O4I2 during reprogramming led to the development of an O4I2 derivative, O4I4, which exhibited resistance to carboxylesterase 1-mediated xenobiotic metabolism. We demonstrated the capacity of O4I4 to replace OCT4 for the generation of iPSCs in the presence of SKML, opening up new avenues for iPSC production. Aligning with recent findings from independent research groups indicating rejuvenation in partially reprogrammed mice, with evidence of reversed aging markers and improved tissue regeneration, O4I4 demonstrated promising results of extending lifespans by 10-20% in C. elegans and Drosophila, suggesting its potential applications in regenerative medicine and anti-aging therapy. Further analysis revealed that splicing factor 3B1 is one of the major targets of O4I4. Conjugating O4I4 on the thalidomide derivative, a CRBN ligand, resulted in the first PROTAC targeting splicing machinery, attracting further investigation from a life science company and a pharmaceutical company group. The successful outcomes of this DFG-funded project have not only enhanced our understanding of reprogramming processes but also opened the door to potential therapeutic applications. The identification and development of O4I4 and related compounds present exciting possibilities for regenerative medicine and anti-aging therapies. This project yielded 28 peer-reviewed publications (between 2016-2023, 19 publications as first/corresponding author) and three patents in collaboration with the University of Heidelberg, further emphasizing the impact of this research in the field.

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