CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy
CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy
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DOI：
10.1158/1078-0432.ccr-09-0152
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发表时间：
2009-06-15
影响因子：
11.5
通讯作者：
Qian, Changgeng
中科院分区：
文献类型：
--
作者：
Bao, Rudi;Lai, Cheng-Jung;Qian, Changgeng
目的：设计并合成了一种新型咪唑并吡啶类HSP 90抑制剂CUDC-305。在这里，我们报告其独特的药理学特性和抗肿瘤活性在各种肿瘤types.Experimental设计：该化合物的效力进行了分析，通过荧光偏振竞争结合试验。在40个人癌细胞系中评估其抗增殖活性。结果：CUDC-305对HSP 90 α/β（IC 50约为100 nmol/L）和癌细胞来源的HSP 90复合物（IC 50为48.8 nmol/L）具有较高的亲和力。它对广泛的癌细胞系显示出有效的抗增殖活性（平均IC 50，220 nmol/L）。与正常组织相比，CUDC-305具有较高的口服生物利用度（96.0%）和在肿瘤中的选择性保留（半衰期，20.4小时）。此外，CUDC-305可以穿过血脑屏障并在脑组织中达到治疗水平。CUDC-305在皮下注射中表现出剂量依赖性抗肿瘤活性。在U87 MG胶质母细胞瘤异种移植模型中，显著降低了动物存活率，并在U87 MG原位模型中显著降低了动物存活率。CUDC-305还在厄洛替尼耐药非小细胞肺癌动物模型中显示出有效的抗肿瘤活性，并在MDA-MB-468乳腺癌和MV 4 -11急性髓性白血病动物模型中诱导肿瘤消退。与其在这些不同肿瘤模型中的功效相关，CUDC-305强烈抑制多种信号传导途径，包括PI 3 K/AKT和RAF/MEK/ERK，并诱导细胞凋亡。在联合研究中，CUDC-305增强了标准护理剂在乳腺癌和结直肠肿瘤model.Conclusion的抗肿瘤活性：CUDC-305是一种有前途的候选药物，用于治疗各种癌症，包括脑恶性肿瘤。
Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types.Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.Results: CUDC-305 shows high affinity for HSP90 alpha/beta (IC50, similar to 100 nmol/L) and HSP90 complex derived from cancer cells (IC50, 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC50, 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models.Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.