Izorlisib

Izorlisib (CH5132799) is an orally active, selective Class I PI3K inhibitor with an IC₅₀ value of 14 nM against PI3Kα. Izorlisib methanesulfonate specifically inhibits Class I PI3K (particularly PI3Kα and its mutants) and blocks the PI3K/Akt/mTOR pathway; this leads to cell cycle arrest at the G1 phase and apoptosis without triggering feedback activation of Akt by competitively binding to the ATP-binding site of PI3K. Izorlisib methanesulfonate can be used in research on cancers harboring PIK3CA mutations or PTEN loss (such as breast, ovarian, prostate, and endometrial cancers)^[1][2]. IC50 & Target:IC50: 14 nM (PI3Kα), 36 nM (PI3Kγ), 120 nM (PI3Kβ), 500 nM (PI3Kδ)^[1] In Vitro:Izorlisib (CH5132799) demonstrates potent and selective inhibition of Class I PI3Ks in cell-free assays (IC₅₀ values: 14 nM for PI3Kα, 6.7 nM for PI3Kα E542K, 5.6 nM for PI3Kα H1047R, 120 nM for PI3Kβ, 500 nM for PI3Kγ, and 36 nM for PI3Kδ) ^[1].
Izorlisib (1 nM-10 μM; 2 h) inhibits PI3K/Akt/mTOR pathway signaling in KPL-4 and BT-474 cells ^[1].
Izorlisib (0.01 nM-10 μM; 24 h) inhibits downstream PI3K signaling pathways in BT-474, SK-OV-3, MDA-MB-453, and HCT116 cells without inducing negative feedback activation of Akt ^[1].
Izorlisib (0.076 nM-10 μM; 4 days) inhibits cell proliferation across 60 tumor cell lines, including those derived from breast, ovarian, prostate, and endometrial cancers ^[1].
Izorlisib (1 μM; 48 h) induces G1 cell cycle arrest and apoptosis in KPL-4 cells ^[1].
Izorlisib inhibites the proliferation of HCT116 (IC₅₀ = 0.20 μM), KPL-4 (IC₅₀ = 0.032 μM), T-47D (IC₅₀ = 0.056 μM), SK-OV-3 (IC₅₀ = 0.12 μM), MFE-280 (IC₅₀ = 0.18 μM), and ME-180 (IC₅₀ = 0.14 μM) cells^[2]. In Vivo:Izorlisib (CH5132799) (0.39-25 mg/kg; p.o.; once daily; 11-13 days) demonstrates significant tumor regression activity in mouse xenograft models of breast cancer harboring PIK3CA H1047R and K111N mutations^[1].
Izorlisib (12.5 mg/kg; p.o.; single dose; 0.5-24 h treatment) inhibits the phosphorylation of Akt and its downstream pathway proteins in a time-dependent manner in KPL-4 and BT-474 breast cancer mouse xenograft models^[1].
Izorlisib (3.13-25 mg/kg; p.o.; once daily; >28 days) exhibits potent tumor growth inhibition and regression activity in mouse xenograft models of ovarian cancer (SK-OV-3), endometrial cancer (MFE-280), PTEN-deficient gastric cancer (GXF97), prostate cancer (PC-3), and KRAS-mutant colorectal cancer (HCT116)^[1].
Izorlisib (12.5 mg/kg; p.o.; once daily; 12 consecutive days) shows synergistic anti-tumor activity when combined with Trastuzumab (HY-P9907) in a Trastuzumab-insensitive KPL-4 breast cancer mouse xenograft model, leading to complete tumor regression^[1].
Izorlisib (12.5 mg/kg and 25 mg/kg; p.o.; once daily; 7-day continuous treatment) demonstrates potent regression of drug-resistant tumors and inhibition of the PI3K/mTOR signaling pathway in a BT-474 breast cancer mouse xenograft model that relapsed after long-term everolimus (HY-10218) treatment^[1].
Izorlisib (25 mg/kg; p.o.; once daily; 11 days) inhibits tumor growth in a human prostate cancer PC-3 mouse xenograft model^[2].
Izorlisib (12.5 mg/kg; p.o.; once daily; 2 weeks on/1 week off or 5 days on/2 days off; 6 weeks) induces potent tumor regression in a human breast cancer KPL-4 mouse xenograft model^[2].