Wang Yanong D, Honores Erick, Wu Biqi, Johnson Steve, Powell Dennis, Miranda Miriam, McGinnis John P, Discafani Carolyn, Rabindran Sridhar K, Cheng Wendy, Krishnamurthy Girija
Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA.
Bioorg Med Chem. 2009 Mar 1;17(5):2091-100. doi: 10.1016/j.bmc.2008.12.046. Epub 2008 Dec 25.
Checkpoint deficiency of malignant cells can be exploited in cancer drug discovery. Compounds that selectively kill checkpoint-deficient cells versus checkpoint-proficient cells can be utilized to preferentially target tumor cells, while sparing normal cells. The protein p21(Wafl/Cipl/Sdi1) (hereafter referred to as p21) inhibits progression of the cell cycle by inhibiting the activity of G1 kinases (cyclin D/cdk4 and cyclin E-cdk2) and the G2 kinase (cyclin B/cdkl) in response to DNA damage or abnormal DNA content. The expression of p21 is often low in human cancer cells due to frequent loss of the upstream activator, p53, and is associated with poor prognosis in some cancer patients. Using an isogenic pair of cell lines, HCT116 (p21+/+) and 80S14 (p21-/-), we have disclosed previously a novel series of pyrazolo[1,5-a]pyrimidines that preferentially kill the p21-deficient cells. We will present the synthesis, biological activities and SAR study of a series of pyrazolo[1,5-a]pyrimidines with an optimized phenyl amide moiety at the C-7 position. The mechanism of action of these compounds will also be discussed.
恶性细胞的检查点缺陷可用于癌症药物研发。与具有正常检查点功能的细胞相比，能选择性杀死检查点缺陷细胞的化合物可用于优先靶向肿瘤细胞，同时使正常细胞免受损伤。蛋白质p21（Wafl/Cipl/Sdi1）（以下简称p21）通过抑制G1激酶（细胞周期蛋白D/细胞周期蛋白依赖性激酶4和细胞周期蛋白E - 细胞周期蛋白依赖性激酶2）以及G2激酶（细胞周期蛋白B/细胞周期蛋白依赖性激酶1）的活性来响应DNA损伤或异常DNA含量，从而抑制细胞周期进程。在人类癌细胞中，由于上游激活因子p53的频繁缺失，p21的表达通常较低，并且在一些癌症患者中与预后不良相关。利用同基因细胞系对HCT116（p21+/+）和80S14（p21-/-），我们先前已公开了一系列新型的吡唑并[1,5 - a]嘧啶，它们能优先杀死p21缺陷细胞。我们将展示一系列在C-7位带有优化苯甲酰胺部分的吡唑并[1,5 - a]嘧啶的合成、生物活性及构效关系研究。还将讨论这些化合物的作用机制。
