Development of a novel PI3Kα/CDK7 potent hybrid inhibitor for Cancer treatment

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Drug Discovery

Background:

• Phosphatidylinositol 3-kinase alpha (PI3Kα) and cyclin-dependent kinase 7 (CDK7) are crucial in multiple cancer types.
• PI3Kα influences CDK7 expression, suggesting a potential for dual inhibition strategies.
• Preliminary data indicated PI3Kα might directly activate CDK7, highlighting them as promising drug targets.

Purpose of the Study:

• To design and synthesize novel hybrid molecules targeting both PI3Kα and CDK7.
• To evaluate the inhibitory activity and cytotoxicity of these compounds.
• To explore the potential of dual inhibition for cancer therapy.

Main Methods:

• Hybrid drug design combining known PI3Kα (Alpelisib) and CDK7 (SY-5609) inhibitors.
• Synthesis of hybrid compounds HY3 and HY5.
• Enzyme inhibition assays and IC50 determination for PI3Kα and CDK7.
• Cytotoxicity screening against various cancer and normal cell lines.
• X-ray structure-based drug design for optimizing hybrid inhibitors.

Main Results:

• HY3 demonstrated potent inhibition of CDK7 (IC50 = 10.8 nM) but weak inhibition of PI3Kα.
• HY5 exhibited dual inhibition with IC50 values of 87.9 nM for PI3Kα and 638 nM for CDK7.
• HY5 showed significant cytotoxicity against HCT116, SKOV3, and MCF7 cancer cells (IC50s 360-820 nM).
• HY5 displayed selective toxicity towards cancer cells compared to normal cell lines, with notable efficacy against MCF7 cells.

Conclusions:

• The developed hybrid inhibitor HY5 effectively targets both PI3Kα and CDK7.
• HY5 demonstrates promising dual inhibitory activity and selective cytotoxicity against cancer cells.
• This dual inhibition strategy holds potential for developing novel anti-cancer therapeutics.