GP262 is a PI3K/mTOR PROTAC degrader targeting PI3Kγ, PI3K, and mTOR, with DC50 values of 42.23 nM and 45.4 nM in MDA-MB-231 cells. It induces degradation of p110α and p110γ with DC50 values of 42.23 nM, 227.4 nM, and 45.4 nM, respectively. GP262 exhibits substantial antiproliferative activity and induces apoptosis (apoptosis) in vitro. It effectively modulates the PI3K/AKT/mTOR signaling pathway and degrades target proteins via the ubiquitin-proteasome system. In vivo, GP262 shows tumor growth inhibition and good biosafety. This compound is useful for research in leukemia and triple-negative breast cancer (TNBC).

p110α:227.4 nM (DC50)

GP262 effectively reduces PI3K and mTOR levels in MDA-MB-231 cells at concentrations of 0-5 μM and over a period of 0-24 hours, an effect that is diminished by 26S proteasome inhibition and blocked by high concentrations of competitors (MG132 and VH032), and depends on VHL recruitment. It significantly inhibits cell proliferation and induces apoptosis in a dose-dependent manner in MDA-MB-231, MCF-7, and MDA-MB-361 cells, with IC50 values of 68.0 nM, 161.6 nM, and 124.2 nM, respectively, achieving maximum inhibition rates (Imax) of 65.4%, 83.4%, and 97.7%. At 200 nM, it suppresses colony-forming ability in MDA-MB-231 cells and inhibits mTOR and PI3Kα in MCF-7 cells with IC50 values of 167.6 nM and 40.0 nM, respectively. GP262 (8-5000 nM, 24 hours) causes a concentration-dependent decrease in PI3Kγ protein levels in THP-1 cells and displays antiproliferative effects in OCI-AML3 (IC50 = 44.3 nM) and THP-1 cells (IC50 = 48.3 nM). When used at 1000 nM for 12 hours, GP262 increases the apoptosis rate to 32.1% in MDA-MB-231 cells. It has dissociation constants (Kd) of 0.867 μM and 0.479 μM for PI3Kα and mTOR, respectively. GP262 induces a polyubiquitination-dependent proteasomal degradation pathway. It exhibits excellent selectivity for the PI3K family and mTOR kinase, causing widespread transcriptomic changes in MDA-MB-231 cells, including differential expression of genes related to cell cycle regulation, cancer-related processes, and apoptosis, indicating notable enrichment and profound impact on cell cycle-related pathways.

GP262 (15 or 25 mg/kg, intraperitoneal injection, administered once daily for 20 consecutive days) effectively reduces the levels of target proteins (PI3K and mTOR) in tumor tissues and significantly inhibits tumor growth in the MDA-MB-231 triple-negative breast cancer xenograft NOD-SCI mouse model, while also demonstrating excellent safety and tolerability without causing notable systemic toxicity or organ damage.