Design, synthesis, and biological evaluation of novel bivalent PI3K inhibitors for the potential treatment of cancer

Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer and has become a key target for cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.

Automated summary

Phosphatidylinositol 3-kinase (PI3K) signaling is a common alteration in cancer and a key target for cancer drug development. In this study, a novel series of bivalent PI3K inhibitors with improved potency and anti-proliferative activity were designed and synthesized. The lead compound showed significant inhibition of the PI3K signal pathway, induction of G1 cell cycle arrest, and inhibition of colony formation and cell migration. It also demonstrated dose-dependent anticancer efficacy in a mouse model.