A recent study has identified promising new compounds for the treatment of triple-negative breast cancer (TNBC), one of the deadliest forms of cancer. TNBC is notoriously difficult to treat due to its aggressive nature, multi-drug resistance, and poor patient compliance. Researchers have focused on the PIK3CA gene mutation, a key driver of TNBC, which causes dysregulation of the cell cycle and promotes cancer cell proliferation.
The study explored novel compounds that selectively inhibit PI3Kα, a protein crucial for TNBC growth. By using fragment-based drug discovery, the researchers screened the ChemDiv fragment library of over 11,000 compounds. Through molecular docking, target selectivity analysis, and advanced simulations, they identified two promising moieties: Djh1 and Djh2. These compounds showed strong potential for selective PI3Kα inhibition with minimal off-target effects.
To improve the efficacy and selectivity of these compounds, the researchers used a bioisosteric replacement strategy. This led to the identification of two bioisosteres, Compound 10 and Compound 06, which demonstrated excellent activity against PI3Kα in computational models. The compounds also showed promising ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles, making them potential candidates for clinical development.
While further in vitro and in vivo studies are required to confirm their effectiveness, the findings represent a significant step forward in developing targeted treatments for TNBC, a cancer with high unmet medical needs. The study offers hope for more effective therapies with fewer side effects for TNBC patients in the future.
Helena Bradbury, EMJ
Reference
Halder D et al. Exploring target selectivity in designing and identifying PI3Kα inhibitors for triple negative breast cancer with fragment-based and bioisosteric replacement approach. Sci Rep. 2025;15(1):1890.
