Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA.
J Med Chem. 2010 Apr 22;53(8):3169-82. doi: 10.1021/jm901783v.
Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110alpha isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kalpha and mTOR, leading to the discovery of PI3Kalpha selective inhibitors (e.g., 9) and dual PI3Kalpha/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kalpha/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
大量证据表明，PI3K/Akt 通路的失调在肿瘤进展中很重要。其机制包括肿瘤抑制因子 PTEN 的功能丧失和人类恶性肿瘤中 PI3K p110alpha 同工型的高频突变。PI3K 与肿瘤发生之间的这种联系使 PI3K 成为癌症治疗的一个有前途的靶点。一系列 4-吗啉代吡咯并嘧啶衍生物被合成并评估为 PI3Kalpha 和 mTOR 的抑制剂，从而发现了 PI3Kalpha 选择性抑制剂（例如 9）和双重 PI3Kalpha/mTOR 激酶抑制剂（例如 46 和 48）。PI3Kalpha/mTOR 双重抑制剂在体外和体内显示出抑制肿瘤细胞生长的作用，并抑制了人乳腺癌细胞系 MDA361 中特定于通路的生物标志物[例如 Akt 在 Thr308（T308）和 Ser473（S473）处的磷酸化]。此外，化合物 46 在 MDA361 人乳腺癌肿瘤异种移植模型中表现出良好的体内疗效。
