Triple-negative breast cancers (TNBCs) are an invasive subtype of breast cancers that phenotypically defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBCs account for about 15%-20% of all diagnosed breast cancer cases and are highly intractable due to its unique molecular profile and distinct metastatic patterns. Although TNBCs can be treated with chemotherapy, but approximately 20% of TNBC patients responds to standard chemotherapy. Recently, the overexpression of epidermal growth factor receptor (EGFR) has been investigated as a substantial target for anti-TNBC agents, however, TNBCs frequently show resistance to EGFR tyrosine kinase inhibitors.<br/>In connection with development of novel EGFR-overexpressing TNBC selective inhibitors, an in-house chemical library was initially screened in TNBC cell line MDA-MB-468 and luminal type breast cancer cell line MCF-7 using a dose dependent MTT assay. A hit compound possessing a 2-anilinopyrimidine structure was identified that exhibited selective cytotoxic activity against MDA-MB-468 cell line. Based on this screening result, we designed and synthesized a novel series of 2-anilinopyrimidine derivatives. An intensive SAR study of synthesized compounds was conducted and the influence of lipophilicity on cytotoxicity was evaluated. In addition, the selectivity of the analogs on the TNBC cell line was confirmed by selectivity index (SI).

Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-negative breast cancer cell line

2019 Spring National Meeting

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