Development of PI3Kα inhibitors for tumor therapy

The PI3K/AKT/mTOR signaling pathway is well known to be involved in cell growth, proliferation, metabolism and other cellular physiological processes. Abnormal activation of this pathway is closely related to tumorigenesis and metastasis. As the starting node of the pathway, PI3K is known to contain 4 isoforms, including PI3K alpha, a heterodimer composed of the catalytic subunit p110 alpha and the regulatory subunit p85. PIK3CA, which encodes p110 alpha, is frequently mutated in cancer, especially breast cancer. Abnormal activation of PI3K alpha promotes cancer cell proliferation, migration, invasion, and angiogenesis; therefore, PI3K alpha has become a key target for the development of anticancer drugs. The hinge region and the region of the mutation site in the PI3K alpha protein are important for designing PI3K alpha-specific inhibitors. As the group shared by the most PI3K alpha-specific inhibitors reported thus far, carboxamide can produce hydrogen bonds with Gln859 and Ser854. Gln859 is specific to the p110 alpha protein in producing hydrogen bond interactions with PI3K alpha-specific inhibitors and this is a key point for designing PI3K alpha inhibitors. To date, alpelisib is the only PI3K alpha inhibitor approved for the treatment of breast cancer. Several other PI3K alpha inhibitors are under evaluation in clinical trials. In this review, we briefly describe PI3K alpha and its role in tumorigenesis, summarize the clinical trial results of some PI3K alpha inhibitors as well as the synthetic routes of alpelisib, and finally give our proposal for the development of novel PI3K alpha inhibitors for tumor therapy. HIGHLIGHTS We summarize the progress of PI3Ka and PI3Ka inhibitors in cancer from the second half of the 20th century to the present. We describe the clinical trial results of PI3Ka inhibitors as well as the synthetic routes of the only approved PI3Ka inhibitor alpelisib. Crystal structure of alpelisib bound to the PI3Ka receptor binding domain. This review gives proposal for the development of novel PI3Ka inhibitors and will serve as a complementary summary to other reviews in the research field of PI3K inhibitors. [GRAPHICAL].