Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer,Journal of Medicinal Chemistry

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Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-26 , DOI: 10.1021/acs.jmedchem.1c00705
Xuan-Ming Guo ₁ , Maruti Balaso Yadav ₂ , Mahjabin Khan ₁ , Chao-Wei Hao ₂ , Cheng-Yuan Lin _{1,

2} , Tao Huang ₁ , Jiang Wu ₃ , Bao-Min Fan ₂ , Zhao-Xiang Bian ₁

Affiliation

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide–drug conjugate (PDC)─bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugate─synthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.

中文翻译：

针对三阴性乳腺癌中异位表达的血管紧张素转换酶的缓激肽增强肽-紫杉醇偶联物

三阴性乳腺癌（TNBC）是乳腺癌的一种异质亚型，预后较差。在这里，我们提出了一种肽-药物偶联物 (PDC)——缓激肽增强肽-紫杉醇 (BPP-PTX) 偶联物——通过琥珀酰接头将 BPP9a 与 PTX 偶联合成。BPP-PTX 靶向 TNBC 细胞上的血管紧张素转换酶 (ACE)。发现 ACE 在两种 TNBC 细胞系中异位表达，但在受体阳性乳腺癌细胞系和健康肾细胞系中均不存在。过表达、敲低和竞争性抑制实验证明了 ACE 介导的 BPP-PTX 细胞毒性。在体内，ACE 阳性肿瘤富含 BPP-PTX，PDC 比普通 PTX 耐受性更好。与普通 PTX 相比，BPP-PTX 在 MDA-MB-468 异种移植雌性裸鼠中表现出更好的肿瘤抑制作用。同时，BPP-PTX 导致较少的体重减轻和白细胞减少毒性。这些结果共同暗示了 BPP-PTX 作为 ACE 阳性 TNBC 的潜在治疗剂的新颖性、有效性和低毒性特征。

更新日期：2021-12-09

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