Hiriyan Jagadheshan, Shivarudraiah Prasad, Gavara Govindarajulu, Annamalai Pazhanimuthu, Natesan Selvakumar, Sambasivam Ganesh, Sukumaran Sunil K
Anthem Biosciences Pvt. Ltd., Bangalore, India.
Micro Therapeutics Research Labs Pvt. Ltd., Chennai, India.
Anticancer Res. 2015 Jan;35(1):229-37.
Histone deacetylase (HDAC) inhibitors are a class of drugs that modulate transcriptional activity in cells and are known to induce cell-cycle arrest and angiogenesis, the major components of tumor cell proliferation. The aim of the present study was to characterize a novel hydroxamic acid-based HDAC inhibitor, PAT-1102, and determine its efficacy and tolerability in pre-clinical models.
HDAC enzyme inhibition was measured using HeLa cell nuclear extracts, and recombinant HDAC enzymes. Antiproliferative activity was assessed in a panel of cancer cell lines. Histone hyper-acetylation status and p21 induction were assessed in HeLa cells by immunoblotting. The effect on apoptosis was tested by caspase-3 activation and detection of cleaved poly-ADP ribose polymerase (PARP). Single-dose pharmacokinetics of the compound were assessed in BALB/c mice following oral and intravenous administration. Antitumor efficacy was evaluated in tumor-bearing mice established from lung and colorectal cancer cells (A549 and HCT116, respectively).
PAT-1102 demonstrated potent HDAC-inhibitory activity and growth-inhibitory properties against a panel of cancer cell lines. The optimized compound PAT-1102 exhibits good aqueous solubility, metabolic stability and a favorable pharmacokinetic profile. Once-daily oral administration of PAT-1102 resulted in significant antitumor activity and was well-tolerated in mice.
Our results indicate that PAT-1102 is a novel, potent, orally available HDAC inhibitor with antiproliferative activity against several human cancer cell lines and antitumor activity in mouse xenograft models. Based on the pre-clinical efficacy and safety profile of PAT-1102, the compound demonstrates significant potential for evaluation as a novel drug candidate for cancer therapy.
组蛋白去乙酰化酶（HDAC）抑制剂是一类可调节细胞转录活性的药物，已知其可诱导细胞周期停滞和血管生成，而这两者是肿瘤细胞增殖的主要组成部分。本研究的目的是对一种新型的基于异羟肟酸的HDAC抑制剂PAT-1102进行特性描述，并确定其在临床前模型中的疗效和耐受性。
使用HeLa细胞核提取物和重组HDAC酶来测定HDAC酶抑制作用。在一组癌细胞系中评估抗增殖活性。通过免疫印迹法评估HeLa细胞中的组蛋白高乙酰化状态和p21诱导情况。通过半胱天冬酶-3激活和检测裂解的聚ADP核糖聚合酶（PARP）来测试对细胞凋亡的影响。在BALB/c小鼠口服和静脉给药后评估该化合物的单剂量药代动力学。在分别由肺癌细胞和结肠癌细胞（A549和HCT116）建立的荷瘤小鼠中评估抗肿瘤疗效。
PAT-1102对一组癌细胞系表现出强大的HDAC抑制活性和生长抑制特性。优化后的化合物PAT-1102具有良好的水溶性、代谢稳定性和良好的药代动力学特征。PAT-1102每日一次口服给药可产生显著的抗肿瘤活性，并且在小鼠中耐受性良好。
我们的结果表明，PAT-1102是一种新型、强效、口服可用的HDAC抑制剂，对多种人类癌细胞系具有抗增殖活性，在小鼠异种移植模型中具有抗肿瘤活性。基于PAT-1102的临床前疗效和安全性概况，该化合物作为一种癌症治疗新药候选物具有显著的评估潜力。
