PROTACPI3Kδ degrader-1 is a covalent PI3Kδ-targeting PROTAC degrader that targets lysine, with a DC50 of 3.98 nM. It exhibits potent antiproliferative activity and selective PI3Kδ inhibition (IC50: 8 nM). Additionally, PROTACPI3Kδ degrader-1 effectively degrades p-AKT, induces cell cycle arrest in the G1 phase, and promotes apoptosis and autophagy. It also significantly suppresses tumor growth in the SU-DHL-6 xenograft mouse model.

PI3Kδ:3.98 nM (DC50)

PROTAC PI3Kδ degrader-1 (Compound B14) exhibits half maximal growth inhibition (GI50) values of 0.17 μM and 0.35 μM in SU-DHL-6 and Pfeiffer cells, respectively, at concentrations ranging from 0.001-10 μM over 72 hours. With a concentration of 10 mM, this compound maintains exceptional stability with 80% remaining after 48 hours. At concentrations of 0.1-1 μM over 6-24 hours, it degrades p-AKT and p110δ in SU-DHL-6 cells in a dose- and time-dependent manner, with a DC50 of 3.98 nM. Utilizing 1-100 nM for 24 hours, it triggers autophagy by increasing the LC3II/LC3I ratio in the same cells. The compound degrades p110δ in SU-DHL-6 cells in a time-dependent manner at 100 nM over 6-24 hours, with degradation effects persisting over time. PROTAC PI3Kδ degrader-1 at 0.1-1 μM for 12 hours shows higher binding affinity for VHL E3 ligase ligand, p110δ, and p-AKT, while its analogues demonstrate weaker antiproliferative activity (GI50: 0.17 vs 0.90 and 0.87 μM). At 100 nM for 12 hours, it degrades p110δ in SU-DHL-6 cells via the ubiquitin-proteasome pathway, which can be reversed by MLN4924 (a ubiquitination inhibitor) and MG132 (a proteasome inhibitor). The compound selectively inhibits PI3Kδ in SU-DHL-6 cells (IC50: 8 nM), showing over 70-fold selectivity over the other three subtypes (IC50 all >589 nM). Its strong degradation effect on p110δ in SU-DHL-6 cells at 1-1000 nM for 24 hours contrasts with its weaker impact on p110α and p110β protein levels (DC50 > 1000 nM), and it exhibits no degradation effect on p110γ. At 0.01-1 μM for 24 hours, the compound increases the proportion of SU-DHL-6 cells in the G1 phase in a dose-dependent manner, significantly inducing cell death and damage.

Compound B14, known as PROTAC PI3Kδ degrader-1, demonstrates significant antitumor activity without notable toxicity in the SU-DHL-6 xenograft mouse model when administered intraperitoneally at a dosage of 2-10 mg/kg every other day for 21 days.