Abstract 4212: SJP1602, a selective and dual inhibitor of FAK and Pyk2 for treatment of triple negative breast cancer
Authors: Lee Kug Hwa , Cho Hyoung Min , Hwang Kwangwoo , Park Yongbin , Hong Sungpyo , Ahn Soon Kil , Ki Min-Hyo 
Published: September 2020

Abstract
Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, classified by a lack of ER and PR, and HER2 overexpression. Attributable to its tumor heterogeneity and a high rate of relapse, TNBC carries poor prognosis accounting for 30% mortality of breast cancer patients. Nevertheless, the current therapeutic options for patients with TNBC are limited to chemotherapy, lacking effective targeted therapies.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase mainly known for its role in tumor progression to a malignant phenotype and its involvement in resistance to conventional therapy. Its over-expression and/or activation is associated with poor survival in various types of cancer including TNBC. With increasing evidence of FAK as a promising therapeutic target in cancer, several small molecule inhibitors targeting FAK are currently on development and among them are defactinib (VS-6063) and GSK2256098, which are currently undergoing clinical investigation in combinatorial approach in solid tumors.
In this study, we represent a novel small molecule inhibitor, SJP1602, targeting FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2). Biochemical kinase profiling of SJP1602 showed its greater selectivity for FAK and Pyk2, compared with VS-6063. Moreover, in vitro evaluation of SJP1602 using 3D spheroid models demonstrated that GI50 values of SJP1602 for spheroid growth of various TNBC cell lines were significantly lower than GI50 values of VS-6063 and GSK2256098. SJP1602 also attenuated spheroid formation along with decreased CD44 expression in MDA-MB-231 cells, implicating its capability to suppress the activity of cancer stem cells. In addition, SJP1602 remarkably reduced the invasive potential of MDA-MB-231 cells in 3D conditions, decreasing levels of the EMT-related protein, snail. More importantly, we confirmed the in vivo antitumor activity of SJP1602 compared with VS-6063 in MDA-MB-231 and BT-549 xenograft mouse models that display mesenchymal tumors with invasive and stem-like phenotype. As the result, SJP1602 exhibited substantial inhibitory effects on tumor growth in both xenograft models. In addition, assessment studies of ADME revealed the excellent plasma stability and liver microsomal metabolic stability of SJP1602 in human. Furthermore, therapeutic index estimated by comparison of AUC at toxic and effective doses was higher than 10, rendering its potential clinical safety and efficacy.
Taken together, these findings suggest SJP1602 as a small molecule inhibitor targeting FAK and Pyk2 with its outstanding selectivity and anti-tumor efficacy. Therefore, SJP1602 could be a promising therapeutic agent for TNBC patients that are resistant to conventional therapy as well as for cancer patients with drug resistance involving FAK activation.
Citation Format: Kug Hwa Lee, Hyoung Min Cho, Kwangwoo Hwang, Yongbin Park, Sungpyo Hong, Soon Kil Ahn, Min-Hyo Ki. SJP1602, a selective and dual inhibitor of FAK and Pyk2 for treatment of triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4212.