PROTACPI3Kα degrader-1 is a PI3Kα-targeting PROTAC degrader (DC50= 0.08 μM) that demonstrates notable selectivity in degrading PI3Kα over the PI3Kβ, PI3Kγ, and PI3Kδ isoforms. It degrades PI3Kα effectively in a time- and concentration-dependent manner and significantly inhibits the phosphorylation of AKT at the Ser473 site. Additionally, PROTACPI3Kα degrader-1 exhibits significant in vivo anticancer efficacy in HGC-27 and DOHH2 xenograft models.

PI3Kα:62 nM

PROTAC PI3Kα degrader-1 (Compound 12) at 1 μM demonstrates weak activity (< 20%) against 79 kinases in T47D breast cancer cells but shows strong inhibition of PIK3CA (> 95%). At concentrations of 0.1-10 μM, it selectively degrades PI3Kα over PI3Kβ, PI3Kγ, and PI3Kδ in T47D cells. This compound exhibits excellent selectivity for PI3Kα degradation across various cancer cell lines, with an IC50 of 0.35 μM in T47D, 1.64 μM in MDA-MB-453, 1.45 μM in HGC-27, 0.37 μM in AGS, 3.38 μM in LNCaP, 1.48 μM in PC3, and 0.69 μM in Pfeiffer cells. PROTAC PI3Kα degrader-1 at concentrations ranging from 0.0032 to 10 μM over 0 to 24 hours degrades PI3Kα in a concentration- and time-dependent manner in T47D and HGC-27 cells. At 1 μM for 20 hours, it degrades PI3Kα via the CRBN-recruited ubiquitin-proteasome pathway in T47D cells. Additionally, at concentrations of 0.1-10 μM for 24 hours, the compound induces G2/M phase cell cycle arrest in a concentration-dependent manner in T47D cells.

PROTAC PI3Kα degrader-1 (Compound 12) (2 μM, 0-60 min) exhibits excellent plasma stability across all tested species, including mice, rats, dogs, monkeys, and humans. In these species, the compound shows moderate to high clearance rates, with half-lives (t 1/2) of 22.6 minutes in mice, 45.7 minutes in rats, 67.6 minutes in dogs, 32.5 minutes in monkeys, and 34.7 minutes in humans, with a strong dependency on NADPH. Additionally, PROTAC PI3Kα degrader-1, administered intraperitoneally at 30-60 mg/kg over 15 consecutive days, demonstrates significant anticancer activity in the HGC-27 xenograft model. Similarly, at 30 mg/kg for 21 consecutive days, it shows notable anticancer effects in the DOHH2 xenograft model.