Unveiling CYH33: A Promising PI3Kα Inhibitor for Advanced Solid Tumor Therapy

A series of pyrrolo[2,1-f][1,2,4]triazines were synthesized to identify novel inhibitors targeting the PI3Kα enzyme, which is often abnormally active in solid tumors. The research resulted in the development of compound 40, known as CYH33, a highly potent and selective PI3Kα inhibitor. CYH33 showed significant efficacy against PI3Kα with low IC50 values compared to other PI3K isoforms, and minimal activity against a panel of over 300 kinases, demonstrating its selectivity. The compound was also found to effectively inhibit the PI3K/AKT/mTOR pathway in various cancer cell lines, particularly those derived from breast cancer, which is known for frequent PI3K hyper-activation.

In vivo studies with mice bearing SKOV-3 ovarian cancer xenografts showed that CYH33 reduced AKT phosphorylation in tumor tissues and significantly inhibited tumor growth without causing substantial weight loss or toxic side effects. Additionally, CYH33 maintained glucose tolerance, with blood glucose levels returning to normal within two hours post-glucose injection. The compound also exhibited a favorable pharmacokinetic profile, including a 36.9% oral bioavailability and minimal interaction with major cytochrome P450 enzymes.

CYH33 has been recognized as a promising candidate for the treatment of advanced solid tumors due to its potent activity, selectivity, and favorable pharmaceutical characteristics, and is currently undergoing clinical trials in China.