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Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-11-30 , DOI: 10.1016/j.bmc.2019.115228 Fangqing Zhang 1 , Zhenwei Wu 1 , Pan Chen 2 , Jian Zhang 1 , Tao Wang 1 , Jinpei Zhou 2 , Huibin Zhang 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-11-30 , DOI: 10.1016/j.bmc.2019.115228 Fangqing Zhang 1 , Zhenwei Wu 1 , Pan Chen 2 , Jian Zhang 1 , Tao Wang 1 , Jinpei Zhou 2 , Huibin Zhang 1
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BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.
中文翻译：
基于二氢喹唑啉酮衍生物和来那度胺/泊马来度胺的新型PROTAC BRD4降解剂的发现。
BRD4已成为抗癌治疗的诱人靶标。但是，BRD4抑制剂的治疗会导致BRD4蛋白质积聚，以及抑制剂与BRD4结合的可逆性，这可能会限制BRD4抑制剂的功效。为了解决这些问题，最近已经开发了基于蛋白水解靶向嵌合体（PROTAC）技术的蛋白质降解策略来靶向BRD4。本文中，我们介绍了新型PROTAC BRD4降解剂的设计，合成和生物学评估，该降解剂基于有效的基于二氢喹唑啉酮的BRD4抑制剂化合物6和来那度胺/泊马来度胺作为E3连接酶脑的配体。令人欣慰的是，几种化合物对BRD4表现出优异的抑制活性，并且对人单核细胞淋巴瘤细胞系THP-1具有很高的抗增殖能力。尤其，化合物21（BRD4 BD1，IC50 = 41.8 nM）在抑制THP-1细胞系生长方面实现了亚微摩尔IC50值为0.81μM，并且是化合物6的4倍。诱导BRD4蛋白降解并抑制c-Myc。所有这些结果表明21是有效的BRD4降解物，需要进一步研究。
更新日期：2019-11-30
中文翻译：
基于二氢喹唑啉酮衍生物和来那度胺/泊马来度胺的新型PROTAC BRD4降解剂的发现。
BRD4已成为抗癌治疗的诱人靶标。但是，BRD4抑制剂的治疗会导致BRD4蛋白质积聚，以及抑制剂与BRD4结合的可逆性，这可能会限制BRD4抑制剂的功效。为了解决这些问题，最近已经开发了基于蛋白水解靶向嵌合体（PROTAC）技术的蛋白质降解策略来靶向BRD4。本文中，我们介绍了新型PROTAC BRD4降解剂的设计，合成和生物学评估，该降解剂基于有效的基于二氢喹唑啉酮的BRD4抑制剂化合物6和来那度胺/泊马来度胺作为E3连接酶脑的配体。令人欣慰的是，几种化合物对BRD4表现出优异的抑制活性，并且对人单核细胞淋巴瘤细胞系THP-1具有很高的抗增殖能力。尤其，化合物21（BRD4 BD1，IC50 = 41.8 nM）在抑制THP-1细胞系生长方面实现了亚微摩尔IC50值为0.81μM，并且是化合物6的4倍。诱导BRD4蛋白降解并抑制c-Myc。所有这些结果表明21是有效的BRD4降解物，需要进一步研究。
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