Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine-Anthracenecarboxyimide as a Payload for Antibody-Drug Conjugate
Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine-Anthracenecarboxyimide as a Payload for Antibody-Drug Conjugate
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作为抗体药物缀合物有效负载的新型杂化分子吡咯并苯并二氮杂卓-蒽甲酰亚胺的设计、合成和生物评价
DOI：
10.1021/acs.jmedchem.2c00471
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发表时间：
2022-08-18
影响因子：
7.3
通讯作者：
Yang，Jinliang
中科院分区：
文献类型：
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作者：
Lai，Weirong;Zhao，Shengyan;Yang，Jinliang
设计、合成了一系列新型的吡咯并苯并二氮杂卓（PBD）和蒽甲酰亚胺（anthracenecarboxyimide）结合的杂合分子，并进行了体外抗肿瘤活性的研究。该系列化合物中活性最强的化合物37 b3表现出亚纳摩尔水平的细胞毒性，IC 50为0.17-0.94 nM.37b3诱导DNA损伤并导致肿瘤细胞周期停滞和凋亡。我们采用37 b3作为有效负载物与曲妥珠单抗偶联，得到抗体-药物偶联物（ADC）T-PBA。T-PBA保持了曲妥珠单抗的靶向模式和内化能力。我们证明T-PBA可以通过溶酶体途径降解，并在内化后释放有效载荷37 b3。T-PBA在体外对Her 2阳性的癌细胞有较强的杀伤作用。此外，T-PBA显著抑制胃癌和卵巢癌异种移植小鼠模型中的肿瘤生长，而没有明显的毒性。总的来说，这些研究表明，T-PBA代表了一种有前途的新ADC，值得进一步研究。
A novel series of hybrid molecules combining pyrrolobenzodiazepine (PBD) and anthracenecarboxyimide pharmacophores were designed, synthesized, and tested forin vitrocytotoxicity against various cancer cell lines. The most potent compound from this series,37b3, exhibited a subnanomolar level of cytotoxicity with an IC50of 0.17–0.94 nM.37b3induced DNA damage and led to tumor cell cycle arrest and apoptosis. We employed37b3as a payload to conjugate with trastuzumab to obtain the antibody–drug conjugate (ADC) T-PBA. T-PBA maintained its mode of target and internalization ability of trastuzumab. We demonstrated that T-PBA could be degraded through the lysosomal pathway to release the payload37b3after internalization. T-PBA showed a powerful killing effect on Her2-positive cancer cellsin vitro. Furthermore, T-PBA significantly inhibited tumor growth in gastric and ovarian cancer xenograft mouse models without overt toxicity. Collectively, these studies suggest that T-PBA represents a promising new ADC that deserves further investigation.