Fan Heli, Zaman Muhammad Asad Uz, Chen Wenbing, Ali Taufeeque, Campbell Anahit, Zhang Qi, Setu Nurul Islam, Saxon Eron, Zahn Nicolas M, Benko Anna M, Arnold Leggy A, Peng Xiaohua
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States.
ACS Pharmacol Transl Sci. 2021 Mar 7;4(2):687-702. doi: 10.1021/acsptsci.0c00092. eCollection 2021 Apr 9.
Triple-negative breast cancer (TNBC) has limited treatment options and the worst prognosis among all types of breast cancer. We describe two prodrugs, namely, CWB-20145 () and its methyl analogue FAN-NM-CH () that reduced the size of TNBC-derived tumors. The DNA cross-linking of nitrogen mustard prodrugs and was superior to that of chlorambucil and melphalan once activated in the presence of HO. The cellular toxicity of and was demonstrated in seven human cancer cell lines. The TNBC cell line MDA-MB-468 was particularly sensitive toward and . Compound was 10 times more cytotoxic than chlorambucil and 16 times more active than melphalan. An evaluation of the gene expression demonstrated an upregulation of the tumor suppressor genes and supporting a transcriptional mechanism of a reduced tumor growth. Pharmacokinetic studies with showed a rapid conversion of the prodrug. The introduction of a methyl group generated with an increased half-life. An in vivo toxicity study in mice demonstrated that both prodrugs were less toxic than chlorambucil. Compounds and reduced tumor growth with an inhibition rate of more than 90% in athymic nude mice xenografted with MDA-MB-468 cells. Together, the in vivo investigations demonstrated that treatment with and suppressed tumor growth without affecting normal tissues in mice. These phenylboronic acid nitrogen mustard prodrugs represent promising drug candidates for the treatment of TNBC. However, the mechanisms underlying their superior in vivo activity and selectivity as well as the correlation between HO level and in vivo efficacy are not yet fully understood.
三阴性乳腺癌（TNBC）的治疗选择有限，在所有类型的乳腺癌中预后最差。我们描述了两种前药，即CWB-20145（）及其甲基类似物FAN-NM-CH（），它们减小了TNBC衍生肿瘤的大小。氮芥前药和在HO存在下一旦被激活，其DNA交联作用优于苯丁酸氮芥和马法兰。和在七种人类癌细胞系中表现出细胞毒性。TNBC细胞系MDA-MB-468对和特别敏感。化合物的细胞毒性比苯丁酸氮芥高10倍，比马法兰高16倍。基因表达评估显示肿瘤抑制基因和上调，支持肿瘤生长减少的转录机制。对的药代动力学研究表明前药能快速转化。甲基的引入产生了半衰期延长的。小鼠体内毒性研究表明，两种前药的毒性均低于苯丁酸氮芥。化合物和在接种MDA-MB-468细胞的无胸腺裸鼠中使肿瘤生长减少，抑制率超过90%。总之，体内研究表明，用和治疗可抑制小鼠肿瘤生长而不影响正常组织。这些苯基硼酸氮芥前药是治疗TNBC的有前景的候选药物。然而，它们体内优越活性和选择性的潜在机制以及HO水平与体内疗效之间的相关性尚未完全了解。
