OSI-027

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

mTORC1 和 mTORC2 的有效选择性抑制剂，IC50 分别为 22 nM 和 65 nM。

A potent and selective inhibitor of mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM, respectively; displays >100-fold selectivity for mTOR over PI3Kα, PI3Kβ, PI3Kγ, and DNA-PK; inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo; demonstrates robust antitumor activity in human xenograft models.Blood Cancer Phase 1 Discontinued(In Vitro):OSI-027 is an ATP-competitive inhibitor, which targets both mTORC1 and mTORC2 with IC50s of 22 nM and 65 nM. OSI-027 also inhibits PI3K-α, PI3K-γ and DNA-PK with IC50s of 1.3 μM, 0.42 μM and 1.0 μM. OSI-027 inhibits mTOR signaling of phospho-4E-BP1 with an IC50 of 1 μM.(In Vivo):Effects on GEO colorectal xenograft growth treated with Rapamycin or OSI-027 for 12 days are consistent with our in vitro experiments. Treatment with Rapamycin (20 mg/kg) inhibits phospho-S6 and phospho-4E-BP1, while Akt phosphorylation is increased by 29%. In contrast, OSI-027 (65 mg/kg) inhibits both mTORC1 and mTORC2 effectors. After 2 hours, decreased 4E-BP1, Akt, and S6 phosphorylation is observed and inhibition of S6 and Akt is sustained for 24 hours. The plasma drug concentration of OSI-027 inversely correlated with these effects on mTORC1 and mTORC2 signaling. The median plasma drug concentration with OSI-027 is 21.3 μM at 2 hours and 14.9 μM at 8 hours. The in vivo efficacy of OSI-027 plus Sunitinib is tested in H292 human lung and Ovcar-5 human ovarian xenograft tumors. H292 tumors, treated with OSI-027 (50 mg/kg) for 21 days have 61% median tumor growth inhibition for the duration of treatment (TGI). Sunitinib (40 mg/kg) for 21 days had 47% median TGI. Combining OSI-027 with Sunitinib, however, has a median TGI of 100% with 59% maximal tumor regression, a statistically significant improvement over either agent alone. Ovcar-5 xenograft tumors treated with OSI-027 or Sunitinib have a 55% and 68% median TGI, respectively. OSI-027 administered with Sunitinib has a significantly better median TGI of 100% with 38% maximal tumor regression.In the Rapamycin (RAPA) group, three rats exhibit symptoms typical of LTx-aGVHD and die 27 to 35 days after liver transplantation (LT); the remaining five rats do not develop LTx-aGVHD symptoms and survive for more than 100 days. In contrast, seven rats in the OSI-027 group survive for more than 100 days without symptoms of LTx-aGVHD, and only one rat exhibits LTx-aGVHD symptoms and dies on day 33 after LT.

OSI-027 is an ATP-competitive inhibitor, which targets both mTORC1 and mTORC2 with IC50s of 22 nM and 65 nM. OSI-027 also inhibits PI3K-α, PI3K-γ and DNA-PK with IC50s of 1.3 μM, 0.42 μM and 1.0 μM. OSI-027 inhibits mTOR signaling of phospho-4E-BP1 with an IC50 of 1 μM.

Effects on GEO colorectal xenograft growth treated with Rapamycin or OSI-027 for 12 days are consistent with our in vitro experiments. Treatment with Rapamycin (20 mg/kg) inhibits phospho-S6 and phospho-4E-BP1, while Akt phosphorylation is increased by 29%. In contrast, OSI-027 (65 mg/kg) inhibits both mTORC1 and mTORC2 effectors. After 2 hours, decreased 4E-BP1, Akt, and S6 phosphorylation is observed and inhibition of S6 and Akt is sustained for 24 hours. The plasma drug concentration of OSI-027 inversely correlated with these effects on mTORC1 and mTORC2 signaling. The median plasma drug concentration with OSI-027 is 21.3 μM at 2 hours and 14.9 μM at 8 hours. The in vivo efficacy of OSI-027 plus Sunitinib is tested in H292 human lung and Ovcar-5 human ovarian xenograft tumors. H292 tumors, treated with OSI-027 (50 mg/kg) for 21 days have 61% median tumor growth inhibition for the duration of treatment (TGI). Sunitinib (40 mg/kg) for 21 days had 47% median TGI. Combining OSI-027 with Sunitinib, however, has a median TGI of 100% with 59% maximal tumor regression, a statistically significant improvement over either agent alone. Ovcar-5 xenograft tumors treated with OSI-027 or Sunitinib have a 55% and 68% median TGI, respectively. OSI-027 administered with Sunitinib has a significantly better median TGI of 100% with 38% maximal tumor regression.In the Rapamycin (RAPA) group, three rats exhibit symptoms typical of LTx-aGVHD and die 27 to 35 days after liver transplantation (LT); the remaining five rats do not develop LTx-aGVHD symptoms and survive for more than 100 days. In contrast, seven rats in the OSI-027 group survive for more than 100 days without symptoms of LTx-aGVHD, and only one rat exhibits LTx-aGVHD symptoms and dies on day 33 after LT.

OSI027 | OSI 027

PI3K/Akt/mTOR signaling

mTOR

DNA-PK| mTOR| mTORC1| mTORC2| PI3Kγ

Cancer

Blood cancer

936890-98-1

406.4378

C21H22N6O3

>98% (HPLC)

10 mM in DMSO

COC1=CC=CC2=C1NC(=C2)C1=C2N(N=CN=C2N)C(=N1)[C@H]1CC[C@@H](CC1)C(O)=O |r,c:4,6,10,16,18,22,t:2,13|

Cyclohexanecarboxylic acid, 4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]-, trans-

(-20℃)

With Ice Pack

≥ 2 years