Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). TNBC is characterized by high heterogeneity, high rates of metastasis and recurrence, poor prognosis, and limited targeted therapeutic strategies. LC129-8 was previously discovered through a phenotypic cell-binding screening of a combinatorial 8-mer peptoid library and was found to display anti-TNBC activity in vitro and in vivo. Although LC129-8 showed highly selective binding to TNBC cell lines and tissues, its anti-TNBC activity was not potent enough to be considered a therapeutic candidate. In our efforts toward developing a more potent derivative of LC129-8, we have started our study to identify the minimal pharmacophore of LC129-8. Sarcosine scanning, an equivalent of alanine scanning in peptide science, was utilized to identify side chains that are responsible and necessary for anti-TNBC activity of LC129-8. Each residue of LC129-8 was replaced, in turn, with sarcosine (N-methylglycine) to generate eight sarcosine-containing derivatives of LC129-8. These derivatives were purified by preparative HPLC and characterized by LC-MS. We are currently examining the activity of these LC129-8 sarcosine derivatives against TNBC cell lines such as MDA-MB-231 and BT-549 to identify the residues of LC129-8 that constitute the minimal pharmacophore of LC129-8. Successful completion of this study will identify the minimal pharmacophore of LC129-8 which can be utilized in future medicinal chemistry to develop low-molecular-weight LC129-8 derivatives as TNBC-targeting therapeutic candidates.

Identification of the minimal pharmacophore of TNBC-targeting peptoid LC129-8

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