JNJ-26481585, a Novel "Second-Generation" Oral Histone Deacetylase Inhibitor, Shows Broad-Spectrum Preclinical Antitumoral Activity
JNJ-26481585, a Novel "Second-Generation" Oral Histone Deacetylase Inhibitor, Shows Broad-Spectrum Preclinical Antitumoral Activity
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DOI：
10.1158/1078-0432.ccr-09-0547
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发表时间：
2009-11-15
影响因子：
11.5
通讯作者：
Angibaud, Patrick
中科院分区：
文献类型：
--
作者：
Arts, Janine;King, Peter;Angibaud, Patrick
目的：组蛋白去乙酰化酶（HDAC）抑制剂在血液恶性肿瘤的治疗中显示出有希望的临床活性，但其在实体瘤适应症中的活性有限。临床开发中的大多数HDAC抑制剂仅瞬时诱导肿瘤组织中的组蛋白乙酰化。在此，我们试图鉴定一种“第二代”I类HDAC抑制剂，其在体内具有延长的药效学反应，以评估这是否会导致上级的抗肿瘤功效。为了鉴定具有上级药效学特性的新型HDAC抑制剂，我们开发了临床前体内肿瘤模型，其中肿瘤细胞已被工程化以表达依赖于HDAC 1抑制的荧光蛋白，结果：140种强效嘧啶基异羟肟酸类似物的体内药效学分析鉴定出JNJ-26481585。JNJ-26481585每日一次经口给药可诱导连续组蛋白H3乙酰化。在Ras突变体HCT 116结肠癌异种移植物中，延长的药效学反应转化为完全的肿瘤生长抑制，而5-氟尿嘧啶活性较低。JNJ-26481585还可完全抑制C170 HM 2结直肠肝转移瘤的生长，而5-氟尿嘧啶/甲酰四氢叶酸也显示出中等活性。进一步表征表明，JNJ-26481585是一种泛HDAC抑制剂，对HDAC 1具有显著的效力（IC（50），0.16 nmol/L）。结论：在临床前模型中作为单药的强效抗肿瘤活性及其良好的药效学特征使JNJ-26481585成为一种有前途的“第二代”HDAC抑制剂。该化合物目前正在进行临床研究，以评估其在广泛的实体和血液恶性肿瘤中的潜在适用性。(Clin Cancer Res 2009;15（22）：6841-51）
Purpose: Histone deacetylase (HDAC) inhibitors have shown promising clinical activity in the treatment of hematologic malignancies, but their activity in solid tumor indications has been limited. Most HDAC inhibitors in clinical development only transiently induce histone acetylation in tumor tissue. Here, we sought to identify a "second-generation" class I HDAC inhibitor with prolonged pharmacodynamic response in vivo, to assess whether this results in superior antitumoral efficacy.Experimental Design: To identify novel HDAC inhibitors with superior pharmacodynamic properties, we developed a preclinical in vivo tumor model, in which tumor cells have been engineered to express fluorescent protein dependent on HDAC1 inhibition, thereby allowing noninvasive real-time evaluation of the tumor response to HDAC inhibitors.Results: In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ-26481585. Once daily oral administration of JNJ-26481585 induced continuous histone H3 acetylation. The prolonged pharmacodynamic response translated into complete tumor growth inhibition in Ras mutant HCT116 colon carcinoma xenografts, whereas 5-fluorouracil was less active. JNJ-26481585 also fully inhibited the growth of C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin showed modest activity. Further characterization revealed that JNJ-26481585 is a pan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L).Conclusions: The potent antitumor activity as a single agent in preclinical models combined with its favorable pharmacodynamic profile makes JNJ-26481585 a promising "second-generation" HDAC inhibitor. The compound is currently in clinical studies, to evaluate its potential applicability in a broad spectrum of both solid and hematologic malignancies. (Clin Cancer Res 2009;15(22):6841-51)