XL388 is a highly potent, selective, ATP-competitive inhibitor of mTOR with IC50 of 9.9 nM, 1000-fold selectivity over the closely related PI3K kinases.

 In MCF7 cells, XL388 blocks mTORC1 phosphorylation of p70S6K (T389)with an IC50 value of 94 nM and blocks mTORC2 phosphorylationof AKT (S473) with an IC50 value of 350 nM. In vitro, XL388 inhibits the viability of solid and hematopoietic tumor cell lines. The proliferation IC50 is 1.37 μM in MCF-7 cell line. XL388 also synergizes with chemotherapeutics in cell-based assays to block cell viability. [1]

 When dosed orally once daily in mice, XL388 shows robust anti-tumor activity in multiple xenograft models including > 100% tumor growth inhibition in the MCF-7 xenograft model. [1] XL388 displays good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. The mean plasma protein binding of XL388 in human, monkey, dog, rat, and mouse plasma is evaluated at 5 μM and is determined to be 86%, 90%, 89%, 85%, and 84%, respectively. Oral administration of XL388 to athymic nude mice implanted with human tumor xenografts afforded significant and dosedependent antitumor activity. Strong inhibition of both mTORC1 and mTORC2 is achieved 4−8 h following administration orally at 100 mg/kg. Modest inhibition (39−45%) of phosphorylation of the PI3K target AKT (T308) is also observed 4−8 h post dose.[2]

 

References

[1] Nicole Miller, et al. Mol Cancer Ther, 2009, 8(12 Suppl):B146.

[2] Takeuchi CS, et al. J Med Chem, 2013, 56(6), 2218-2234.

转载本文请联系原作者获取授权，同时请注明本文来自陈达科学网博客。
链接地址：https://wap.sciencenet.cn/blog-2321593-930294.html

上一篇：Omipalisib (GSK2126458, GSK458)
下一篇：Entinostat (MS-275) strongly inhibits HDAC1 and HDAC3