化学
Wnt信号通路
药物发现
酪蛋白激酶1
小分子
信号转导
药理学
激酶
生物化学
蛋白激酶A
细胞生物学
生物
作者
Zhiqing Liu,Pingyuan Wang,Eric A. Wold,Qiaoling Song,Chenyang Zhao,Chang‐Yun Wang,Jia Zhou
标识
DOI:10.1021/acs.jmedchem.0c01799
摘要
Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the production and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein–protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clinical trials. Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.
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