CYH33 methanesulfonate 是一种具有口服活性的，高选择性PI3Kα抑制剂，对 α/β/δ/γ 亚型的IC50分别为 5.9 nM/598 nM/78.7 nM/225 nM。CYH33 methanesulfonate 抑制 Akt 和 ERK 的磷酸化，并显着诱导乳腺癌和非小细胞肺癌 (NSCLC) 细胞 G1 期阻滞。CYH33 methanesulfonate 具有有效的抗实体瘤的活性。
| 生物活性 | CYH33 methanesulfonate is an orally active, highly selectivePI3Kαinhibitor withIC50s of 5.9 nM/598 nM/78.7 nM/225 nM against α/β/δ/γ isoform, respectively. CYH33 methanesulfonate inhibits phosphorylation ofAkt,ERKand induces significant G1 phase arrest in breastcancercells and non-small cell lungcancer(NSCLC) cells. CYH33 methanesulfonate has potent activity against solid tumors[1][2][3]. |
| IC50& Target[1] | PI3Kα 5.9 nM (IC50) | PI3Kβ 598 nM (IC50) | PI3Kδ 78.7 nM (IC50) | PI3Kγ 225 nM (IC50) |
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体外研究
(In Vitro) | CYH33 methanesulfonate inhibits cell proliferation with IC50s below 1 μM in 56% (18/32) of the breast cancer cell lines[2].
CYH33 (0.012-1 μM; for 24 hours) methanesulfonate significantly arrests T47D and MCF7 cells in G1 phase in a concentration-dependent manner[2].
CYH33 (4-1000 nM; 1 hour) methanesulfonate concurrently inhibits phosphorylation of ERK and Akt in both T47D and MCF7 cells[2].
CYH33 (0.11-1 μM; 24 hours) methanesulfonate 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. |
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体内研究
(In Vivo) | CYH33 (2-20 mg/kg; oral; once a day for 21 days) methanesulfonate potently restrains tumor growth in mice bearing human breast cancer cell xenografts[2].
Single administration of CYH33 (20 mg/kg; oral) methanesulfonate 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) methanesulfonate delays the restoration of blood glucose and area under the curve (AUC) of blood glucose increased upon CYH33 treatment in T47D xenografts and R26-Pik3caH1047R;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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
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