Pyrazolopyrimidine scaffold yields dual PI3K/HDAC6 inhibitors active across breast cancer subtypes
- Pairing PI3K and HDAC inhibition on a pyrazolo[3,4-d]pyrimidine core targets crosstalk between the PI3K/AKT pathway and epigenetic dysregulation in breast cancer.
- Lead compound 13k inhibits PI3Kα at sub-micromolar potency and HDAC6 at low-nanomolar potency; pharmacophore modeling, docking and molecular dynamics rationalized the SAR.
- In ER+, HER2+ and triple-negative lines it curbed proliferation, migration and invasion, and triggered apoptosis and G1 arrest; predicted ADMET looked drug-like.
💡 Points Based on the abstract
Unlike CUDC-907, which hits class I HDACs plus PI3K, 13k leans on HDAC6, a cleaner and likely better-tolerated profile if the selectivity holds. But I'd want a PI3Kα/β/δ/γ and HDAC1/2/3 panel, plus cellular readouts (p-AKT, acetyl-tubulin versus acetyl-H3) to prove on-target engagement. Cell data in three subtypes with only predicted ADMET means hydroxamate PK and mutagenicity are still untested.