Targeting FAK and Pyk2 with SJP1602: A Promising Therapeutic Approach for Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is a highly aggressive form of breast cancer characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression and the lack of HER2 amplification. Due to its tumor heterogeneity and tendency to recur, TNBC is associated with a poor prognosis and contributes to a significant portion of breast cancer-related deaths. Currently, chemotherapy is the primary treatment option for TNBC, with limited targeted therapy options available.

Focal adhesion kinase (FAK) is a protein that plays a key role in the progression of cancer and resistance to traditional treatments. Overexpression or activation of FAK is linked to poor outcomes in various cancers, including TNBC. As a result, FAK has emerged as a potential therapeutic target, with several small molecule inhibitors being developed. Defactinib and GSK2256098 are two such inhibitors that are currently in clinical trials for use in combination with other treatments for solid tumors.

This research introduces a new small molecule inhibitor, SJP1602, which targets FAK and its related protein, Proline-rich tyrosine kinase 2 (Pyk2). SJP1602 has shown greater selectivity for FAK and Pyk2 compared to other inhibitors like VS-6063. In vitro tests using 3D spheroid models have demonstrated that SJP1602 is more effective at inhibiting the growth of TNBC cell lines than VS-6063 and GSK2256098. The inhibitor also reduced the formation of spheroids and decreased CD44 expression in MDA-MB-231 cells, indicating its potential to target cancer stem cells. Furthermore, SJP1602 significantly decreased the invasiveness of MDA-MB-231 cells and lowered the levels of the EMT-related protein, snail. In vivo studies in mouse models showed that SJP1602 is more effective than VS-6063 at inhibiting tumor growth in TNBC.

Pharmacokinetic studies have indicated that SJP1602 has excellent stability in human plasma and liver microsomes, and its therapeutic index, calculated by comparing the area under the curve (AUC) at toxic and effective doses, is greater than 10, suggesting its potential for clinical safety and efficacy.

In conclusion, SJP1602's high selectivity and anti-tumor efficacy make it a promising candidate for the treatment of TNBC, particularly for patients who are resistant to conventional therapies or have cancers with drug resistance involving FAK activation.