The phosphatidylinositol 3-kinase (PI3K) pathway is an essential intracellular signal transduction axis that plays a pivotal role in cancer occurrence and development, for which targeting the PI3K pathway is being intensively investigated for cancer therapeutics. Recently, a research team led by Prof. Heng Xu and Prof. Xiaoguang Chen from Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, discovered novel drug candidates targeting the PI3K pathway and published a series of research papers in J. Med. Chem.Through rational drug design, the research team reported a novel series of 2-amino-4-methylquinazoline derivatives with superior PI3K inhibitory potencies, excellent antitumor efficacies, as well as favorable druggability profiles. And some compounds can even penetrate through the blood-brain barrier (J. Med. Chem. 2018, 61, 6087-6109).Based on this work, the research team designed, synthesized and evaluated a series of PI3K/HDAC dual inhibitors by using a polypharmacological approach. Through systematic structure-activity relationship studies, several lead compounds with nanomolar PI3K/HDAC inhibitory potencies and synergistic antitumor activities were identified for further preclinical development. The related work was published as a cover paper in J. Med. Chem. with Kehui Zhang and Fangfang Lai as co-first authors (J. Med. Chem. 2019, 62, 6992-7014).
In addition to cancer, the research team also explored the therapeutic effect of PI3K inhibitors on idiopathic pulmonary fibrosis (IPF). IPF is a serious and fatal lung disease with median survival ranging from 2.5 to 3.5 years after diagnosis. The PI3K inhibitors with a 4-methylquinazoline skeleton discovered by the team displayed marked antiproliferative activity in mouse MLg2908 lung fibroblasts and were able to improve lung function and pathological damage, reduce hydroxyproline content and α-SMA levels in lung tissues in a bleomycin-induced pulmonary fibrosis mouse model. Therefore, these PI3K inhibitors have potential therapeutic effects on IPF and are worthy of further development. The related work was published as a cover paper in J. Med. Chem. with Songwen Lin, Jing Jin and Ying Liu as co-first authors (J. Med. Chem. 2019, 62, 8873-8879).
Link to article：
https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00416
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00390
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00969
