Pictilisib

Lynch syndrome (LS) is a hereditary disorder that increases the risk of colorectal cancer (CRC) due to constitutional pathogenic variants in mismatch repair (MMR) genes. When coupled with somatic mutations in the same gene, MMR deficiency occurs. However, the mechanisms driving cancer development remain unclear. This study aimed to identify distinct molecular drivers in LS‐associated and sporadic CRC. We found that PI3K–Akt signalling is dysregulated in LS‐associated CRC, while Wnt signalling predominates in sporadic CRC. Moreover, our findings highlight the therapeutic potential of PI3K–Akt pathway inhibitors, such as taselisib, for LS‐associated CRC patients with high pathway dependency. Similarly, Wnt signalling pathway inhibitors, such as XAV939, offer a promising therapeutic approach for sporadic CRC. These findings underscore the importance of understanding the biological basis of disease for developing targeted therapies tailored to CRC subtype‐specific oncogenic pathways.

Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.