GP262

GP262 is a PI3K/mTOR PROTAC degrader targeting PI3Kγ, PI3Kα and mTOR with DC₅₀ values of 42.23 nM, 227.4 nM and 45.4 nM, respectively in MDA-MB-231 cells. GP262 induces degradation of p110α and p110γ with a DC₅₀ of 227.4 and 42.23 nM. GP262 efficient modulates the PI3K/AKT/mTOR pathway, achieving degradation through the ubiquitin-proteasome system (UPS). GP262 also exhibits robust antiproliferative activity and induces apoptosis in vitro. GP262 exhibits tumor growth suppression capability and biosafety profile. GP262 can be used for leukemia and triple-negative breast cancer (TNBC) ^[1]. (Pink: mTOR and PI3K ligand; Blue: VHL ligand; Black: linker).

In Vivo, GP262 (15 or 25 mg/kg, i.p., daily for 20 consecutive days) effective reduces target protein levels (PI3K and mTOR) in tumor tissues and significant tumor growth inhibition and exhibits excellent safety and tolerability without causing significant systemic toxicity or organ damage in MDA MB-231 triple-negative breast cancer xenograft NOD-SCID mice model^[1].

In Vitro, GP262 (0-5 μM, 0-24 h) efficiently reduces PI3K and mTOR Levels and this degradation is attenuated upon 26S proteasome inhibition, can be blocked under high concentration competition (MG132 and VH032 ) and depends on VHL recruitment in MDA-MB-231 cells^[1]. GP262 (8-1000 nM) significantly inhibits proliferation and induces programmed cell death (apoptosis), reveals dose-dependent growth inhibition with IC₅₀ values of 68.0 nM (in MDA-MB-231), 161.6 nM (in MCF-7), and 124.2 nM (in MDA-MB-361), achieving maximum inhibition (Imax) of 65.4, 83.4, and 97.7% respectively, impairs colony formation in MDA-MB-231 cells at 200 nM, and has a degradation efficacy against mTOR and PI3Kα with IC₅₀ values of 167.6 and 40 nM in MCF-7 cells^[1]. GP262 (8-5000 nM, 24 h) demonstrates concentration-dependent reduction of PI3Kγ protein levels in THP-1 cells and antiproliferative effects in OCI-AML3 (IC₅₀ = 44.3 nM) and THP-1 cells (IC₅₀ = 48.3 nM)^[1]. GP262 (1000 nM, 12 h) increases apoptosis to 32.1% in MDA-MB-231 cells^[1]. GP262 (0.03125-2 μM) reveals dissociation constants with Kd of 0.867 μM for PI3Kα and 0.479 μM for mTOR^[1]. GP262 induces polyubiquitination-dependent proteasomal degradation^[1]. GP262 exhibits excellent kinase selectivity for the PI3K family and mTOR, thereby inducing widespread transcriptomic alterations including multiple differentially expressed genes (DEGs) associated with cell cycle regulation, cancer-related processes, and apoptosis, which collectively demonstrate significant enrichment and profound impact on cell cycle-related pathways in MDA-MB-231 cells^[1].

References:
[1]. Zhu W, et al. Discovery of the First Potent PI3K/mTOR Dual-Targeting PROTAC Degrader for Efficient Modulation of the PI3K/AKT/mTOR Pathway. J Med Chem. 2025 Dec 25;68(24):26188-26205.