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

ABSTRACT

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.