Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC50. PHA-848125–treated cells show cell cycle arrest in G1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243–54. ©2010 AACR.

中文翻译：

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口服抑制剂 PHA-848125（一种具有广谱抗肿瘤功效的药物）对 CDK 和原肌球蛋白受体激酶家族的双重靶向

在多种肿瘤中观察到细胞周期蛋白依赖性激酶 (CDK) 和原肌球蛋白受体激酶 (TRK) 家族的表达和活性改变。在那些 CDK 激活异常的恶性肿瘤中，视网膜母细胞瘤蛋白 (pRb) 通路失调，导致细胞增殖失控。相反，TRK 的组成性激活与癌细胞存活和传播有关。在这里，我们展示了新型小分子 PHA-848125，一种有效的 CDK 和 TRK 双重抑制剂，具有显着的抗肿瘤活性。该化合物以亚微摩尔 IC50 抑制多种肿瘤细胞系的细胞增殖。PHA-848125 处理的细胞在 G1 期显示细胞周期停滞和 DNA 合成减少，伴随着 pRb 磷酸化的抑制和其他 CDK 依赖性标志物的调节。该化合物还抑制细胞中 TRKA 及其底物的磷酸化，这些细胞在功能上表达了这种受体。口服给药后，PHA-848125 在各种人类异种移植物和致癌物诱导的肿瘤以及播散性原发性白血病模型中具有显着的抗肿瘤活性，啮齿类动物的血浆浓度与在抑制癌细胞增殖方面具有活性的浓度范围相同。作用机制也在体内得到证实，正如在治疗小鼠的肿瘤活检中所评估的那样。这些结果表明，双重 CDK-TRK 抑制剂 PHA-848125 有可能成为一种新型有效的癌症治疗靶向药物。摩尔癌症治疗; 9(8); 2243-54。©2010 AACR。PHA-848125 在各种人类异种移植物和致癌物诱导的肿瘤以及播散性原发性白血病模型中具有显着的抗肿瘤活性，啮齿类动物的血浆浓度与在抑制癌细胞增殖方面具有活性的浓度范围相同。作用机制也在体内得到证实，正如在治疗小鼠的肿瘤活检中所评估的那样。这些结果表明，双重 CDK-TRK 抑制剂 PHA-848125 有可能成为一种新型有效的癌症治疗靶向药物。摩尔癌症治疗; 9(8); 2243-54。©2010 AACR。PHA-848125 在各种人类异种移植物和致癌物诱导的肿瘤以及播散性原发性白血病模型中具有显着的抗肿瘤活性，啮齿类动物的血浆浓度与在抑制癌细胞增殖方面具有活性的浓度范围相同。作用机制也在体内得到证实，正如在治疗小鼠的肿瘤活检中所评估的那样。这些结果表明，双重 CDK-TRK 抑制剂 PHA-848125 有可能成为一种新型有效的癌症治疗靶向药物。摩尔癌症治疗; 9(8); 2243-54。©2010 AACR。作用机制也在体内得到证实，正如在治疗小鼠的肿瘤活检中所评估的那样。这些结果表明，双重 CDK-TRK 抑制剂 PHA-848125 有可能成为一种新型有效的癌症治疗靶向药物。摩尔癌症治疗; 9(8); 2243-54。©2010 AACR。作用机制也在体内得到证实，正如在治疗小鼠的肿瘤活检中所评估的那样。这些结果表明，双重 CDK-TRK 抑制剂 PHA-848125 有可能成为一种新型有效的癌症治疗靶向药物。摩尔癌症治疗; 9(8); 2243-54。©2010 AACR。