Assessment of Phenylboronic Acid Nitrogen Mustards as Potent and Selective Drug Candidates for Triple-Negative Breast Cancer.

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.