Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGF β1R1 inhibitor

In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-β1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.PMID:38626523 | DOI:10.1016/j.ejmech.2024.116395

Source: European Journal of Medicinal Chemistry - April 16, 2024 Category: Chemistry Authors: Yubo Wang Yulin Liu Yan Zhang Zixuan Zhang Lei Xu Jiefu Wang Yijie Yang Biyu Hu Yuhong Yao Mingming Wei Junfeng Wang Bencan Tang Kun Zhang Shuangwei Liu Guang Yang Source Type: research