发现一种选择性催化p300/CBP抑制剂,可针对特定基因的瘤
Loren M Lasko1, Clarissa G Jakob1, Rohinton P Edalji1
1Discovery, Global Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, USA.
Nature
|September 28, 2017
概括
一种新的药物,A-485,强烈而选择性地抑制像p300和CBP这样的酸转移酶 (HAT),为转录激活剂驱动的癌症提供了有前途的治疗方法.
科学领域:
- 表观遗传学和分子生物学
- 癌症治疗方法
- 药物发现
背景情况:
- 蛋白质乙化,由基因素乙转移酶 (HATs) 和基因素脱乙酶 (HDACs) 调节,是控制基因转录和涉及疾病的关键表观遗传机制.
- 虽然HDAC抑制剂已被批准用于癌症治疗,但由于当前药物效能和选择性的限制,开发有效的HAT抑制剂,特别是p300和CREB结合蛋白 (CBP) 具有挑战性.
- p300/CBP是关键的转录辅助激活剂,参与许多细胞功能,在癌症中经常出现失调.
研究的目的:
- 开发和描述一种针对p300和CBP的催化活性的新型,强效和选择性小分子抑制剂.
- 阐明新型抑制剂在p300催化活性位点内的结合机制.
- 评估该抑制剂在临床前癌症模型中的治疗潜力,重点是血液恶性瘤和前列腺癌.
主要方法:
- 一种新的小分子抑制剂A-485的设计和合成.
- 用A-485复合的p300的高分辨率共同晶体结构的确定.
- 生物化学试验以评估抑制剂的强度,选择性和作用机制 (例如与乙-CoA的竞争).
- 在各种癌细胞系中进行体外增殖测定.
- 使用耐除前列腺癌异种移植模型的体内疗效研究.
主要成果:
- A-485被确定为p300和CBP催化活性的强有力的选择性抑制剂.
- 共同晶体结构显示A-485与催化活性部位结合并与乙-CoA竞争.
- 在特定的癌症类型中,包括血液性恶性瘤和雄激素受体阳性前列腺癌中,A-485被证明具有选择性抑制作用.
- 在体内,A-485抑制了雄激素受体转录程序,并降低了割抵抗性前列腺癌模型的瘤生长.
结论:
- 小分子抑制 histone乙转移酶的催化活性是可行的,并且可以高度选择性.
- A-485代表了治疗由p300/CBP活动驱动的恶性瘤,特别是前列腺癌等某些癌症的有前途的治疗方法.
- 针对HAT提供了一个可行的策略,用于开发转录激活器驱动疾病的新型抗癌疗法.
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