InSilico Medicine, a clinical stage biotechnology company based on generative artificial intelligence (AI), announced today that the Journal of Medicinal Chemistry, a publication by ACS Publications focusing on critical studies of molecular structure and biological activity, has published the company’s discovery of a novel PHD inhibitor for the treatment of anemia. This academic breakthrough is enabled by Chemistry42, its proprietary platform for generative chemistry consisting of more than 40 selected generative models.
As previously suggested in studies, inhibition of Prolylhydroxylase domain enzymes (PHD) influences fundamental biological processes, including the production of red blood cells, by regulating the Nobel Prize-winning HIF-α signaling pathway, indicating potential for the treatment of CKD-induced anemia.
Guided by a structure-based drug discovery strategy (SBDD), researchers at Insilico collected structural information about the PHD target and known molecules, and generated a series of molecule candidates using Chemie42. Using integrated filters covering drug-likeness, pharmacophore clues, synthesis evaluation, and more, the AI-generated candidates were classified and prioritized before a lead compound was created for further optimization.
„Thanks to Chemistry42, we had comprehensive support from molecule generation to proper compound selection. With the power of generative artificial intelligence, we could speed up the drug development process without compromising on novelty or quality.“
– Xiaoyu Ding, Computer Chemist and Lead Author
Subsequent rounds of synthesis testing resulted in lead compound 15, showing a favorable effect on in vitro/in vivo ADMET profile, a clean safety profile, and promising PK properties in multiple species. Furthermore, it was demonstrated in a rat disease model to alleviate anemia with relatively simple synthesis steps.
„Given that more than 10% of the world’s population suffers from CKD, the novel molecule from Insilico could be of significance for further investigations and patients worldwide,“ said Jianyu Xu, the medicinal chemist who co-authored the paper. „After extensive research on already available PHD inhibitors on the market, we hope to develop a novel non-carboxylic acid molecule for better permeability and PK profiles.“
Xu, J., et al. (2024). Discovery of novel and potent inhibitors of Prolylhydroxylase domain-containing protein (PHD) for the treatment of anemia. Journal of Medicinal Chemistry. doi.org/10.1021/acs.jmedchem.3c01932.