Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome
Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome
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DOI：
10.1158/0008-5472.can-06-4086
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Bennett, Mark K.
中科院分区：
文献类型：
--
作者：
Demo, Susan D.;Kirk, Christopher J.;Bennett, Mark K.
硼替佐米的临床研究已经验证了蛋白酶体作为治疗多发性骨髓瘤和非霍奇金淋巴瘤的治疗靶点。然而，显著的毒性限制了硼替佐米给药的强度。在这里，我们描述了PR-171的抗肿瘤活性，PR-171是一种新型的基于环氧酮的不可逆蛋白酶体抑制剂，目前正在临床开发中。与硼替佐米相比，PR-171表现出相同的效力，但对蛋白酶体的胰凝乳蛋白酶样活性具有更大的选择性。在细胞培养中，PR-171在模拟两种分子的体内药代动力学的短暂治疗后比硼替佐米更具细胞毒性。血液肿瘤细胞对短暂暴露表现出最大的敏感性，而实体瘤细胞和非转化细胞类型对此类治疗不太敏感。PR-171处理的细胞后果包括蛋白酶体底物的积累和诱导细胞周期停滞和/或细胞凋亡。PR-171对动物给药导致除脑外检查的所有组织中胰凝乳蛋白酶样蛋白酶体活性的剂量依赖性抑制。当以导致血液和大多数组织中> 80%蛋白酶体抑制的剂量连续给药2天或5天时，PR-171耐受性良好。在人肿瘤异种移植模型中，PR-171介导的抗肿瘤反应具有剂量和时间依赖性。连续2天递送的PR-171的抗肿瘤功效强于按其临床给药方案施用的硼替佐米。这些研究显示了PR-171的耐受性、疗效和剂量灵活性，并为使用剂量密集方案治疗血液恶性肿瘤的PR-171临床试验提供了验证。
Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development. In comparison to bortezomib, PR-171 exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome. In cell culture, PR-171 is more cytotoxic than bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of PR-171 treatment include the accumulation of proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of PR-171 to animals results in the dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissues examined with the exception of the brain. PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in > 80% proteasome inhibition in blood and most tissues. In human tumor xenograft models, PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of PR-171 delivered on 2 consecutive days is stronger than that of bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies using dose-intensive schedules.