CYH33, an orally active and highly selective PI3Kα inhibitor, demonstrates specificity with IC50 values of 5.9 nM for the α isoform, 598 nM for β, 78.7 nM for δ, and 225 nM for γ. It effectively inhibits Akt and ERK phosphorylation and induces substantial G1 phase arrest in breast cancer and non-small cell lung cancer (NSCLC) cells, showcasing potent activity against solid tumors.

PI3Kβ:598 nM (IC50), PI3Kγ:225 nM (IC50), PI3Kα:5.9 nM (IC50), PI3Kδ:78.7 nM (IC50)

CYH33 inhibits cell proliferation with IC 50 s below 1?μM in 56% (18/32) of the breast cancer cell lines[2]. CYH33 (0.012-1 μM; for 24 hours) significantly arrests T47D and MCF7 cells in G1 phase in a concentration-dependent manner[2]. CYH33 (4-1000 nM; 1 hour) concurrently inhibits phosphorylation of ERK and Akt in both T47D and MCF7 cells[2]. CYH33 (0.11-1 μM; 24 hours) fails to induce apoptosis in MCF7 and MDA-MB-231?cells[2]. Cell Cycle Analysis[2]Cell Line: Sensitive T47D, MCF7 and resistant MDA-MB-231 cells Concentration: 0.012, 0.037, 0.11, 0.33, 1 μM Incubation Time: For 24 hours Result: Arrested T47D and MCF7 cells in G1 phase in a concentration-dependent manner, accompanied with concomitant reduced cell population in S phase. Had little effect on cell cycle distribution in resistant MDA-MB-231?cells. Western Blot Analysis[2]Cell Line: Sensitive T47D, MCF7 and resistant MDA-MB-231 cells Concentration: 4, 12, 37, 111, 333, 1000 nM Incubation Time: 1 hour Result: Concurrently inhibited phosphorylation of ERK and Akt in both T47D and MCF7 cells, whereas it had little effect on phosphorylated ERK (pERK) in MDA-MB-231?cells up to 1?μM.

CYH33 (2-20 mg/kg; oral; once a day for 21 days) potently restrains tumor growth in mice bearing human breast cancer cell xenografts[2]. Single administration of CYH33 (20?mg/kg; oral) significantly down-regulates the level of phosphorylated Akt in tumor tissues, demonstrating the suppression of PI3K signaling in nude mice[2]. CYH33 (10?mg/kg; oral; once a day for 18-d or 20-d respectively) delays the restoration of blood glucose and area under the curve (AUC) of blood glucose increased upon CYH33 treatment in T47D xenografts and R26-Pik3ca H1047R ;MMTV-Cre mice[2]. Animal Model: SCID mice aged 4-6 weeks bearing human breast cancer T47D xenografts[2]Dosage: 2, 5, 10, 20 mg/kg Administration: Oral; once a day for 21 days Result: Displayed marginal inhibitory effect on the tumor growth at lower doses (2 and 5?mg/kg) and significantly attenuated tumor growth at the dose of 10 or 20?mg/kg, yielding T/C values of 58.36% and 49.42% respectively.