Clinical-stage genetic artificial intelligence (AI)-driven biotechnology company InSilico Medicine (“InSilico”) today announced that the Journal of Medicinal Chemistry, an ACS Publications journal focused on critical studies of molecular structure and biological activity, published the company’s discovery of a new PHD inhibitor for the treatment of anemia. Academic discovery is powered by Chemistry42, its proprietary genetic chemistry platform consisting of more than 40 selected production models.
As suggested in previous studies, inhibition of prolyl hydroxylase domain (PHD) enzymes affects fundamental biological processes, including red blood cell production, by modulating the Nobel Prize-winning HIF-α pathway, thus indicating potential for the treatment of anemia caused by from CKD.
Guided by a structure-based drug discovery (SBDD) strategy, Insilico scientists gathered structure information for the target PHD and known molecules and generated series of candidate molecules with the help of Chemistry42. Using built-in filters covering drug similarity, pharmacophore indications, composition evaluation and more, AI-generated candidates were ranked and prioritized before a hit compound was produced for further optimization.
Thanks to Chemistry42, we had end-to-end help from molecule creation to compound selection. With the power of genetic AI, we could accelerate the drug discovery process without compromising innovation or quality.”
Xiaoyu Ding, computational chemist who shares first authorship
Subsequently, several rounds of synthesis trial optimization yielded lead compound 15 , which showed favorable in vitro/in vivo ADMET profile, clean safety profile and promising PK properties in many species. Furthermore, the compound was shown to alleviate anemia in a rat model of the disease, with relatively simple synthesis steps.
“Given that more than 10% of the world’s population suffers from CKD, Insilico’s new molecule could be important for further research and patients around the world,” said Jianyu Xu, the pharmacist who authored the paper. “After comprehensive research on PHD inhibitors already available on the market, we hope to develop a new non-carboxylic acid molecule for better permeability and PK profile.”
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Journal Reference:
Xu, J., et al. (2024). Discovery of novel and potent inhibitors of prolyl hydroxylase domain (PHD)-containing protein for the treatment of anemia. Journal of Medicinal Chemistry. doi.org/10.1021/acs.jmedchem.3c01932.
