Defactinib hydrochloride is a small molecule kinase inhibitor that selectively inhibits FAK and Pyk2 [1]. Defactinib hydrochloride inhibits FAK autophosphorylation (e.g., at Tyr397) and blocks integrin-mediated downstream RAS/MEK/ERK and PI3K/Akt signaling pathways, thereby inhibiting tumor cell proliferation, migration, survival, and angiogenesis [2-3]. Defactinib hydrochloride is commonly used to treat recurrent KRAS-mutant low-grade serous ovarian cancer [4].
In esophageal squamous cell carcinoma, Defactinib hydrochloride (0-25μM; 72h) significantly inhibited the growth of tumor cells [5]. In A549 cells, Defactinib hydrochloride (1μM; 48h) partially abolished G9a-enhanced invasion in cells [6].
In NCI-H358 cells xenograft tumor mice model, Defactinib hydrochloride (10mg/kg; ig; 28d) monotherapy inhibits tumor growth [7]. In A427 cells xenograft tumor mice model, Defactinib hydrochloride (10mg/kg; ip; 21d) inhibits tumor growth [8].
References:
[1]. Moore K, Walter A. Defactinib hydrochloride. Dual FAK1/PYK2 inhibitor, Treatment of non-small cell lung cancer, treatment of malignant mesothelioma, treatment of ovarian cancer[J]. Drugs of the Future, 2014, 39(11).
[2]. Ryzhakov G, Almuttaqi H, Corbin A L, et al. Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation[J]. Nature Communications, 2021, 12(1): 6702.
[3]. Riordan J D, Nathanson T A, Varzavand A, et al. A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition[J]. bioRxiv, 2024: 2024.12. 22.629990.
[4]. Banerjee S N. Avutometinib/Defactinib May be a New SOC in Low-Grade Serous Ovarian Cancer[J]. Cancer Network, 2023: NA-NA.
[5]. Zhang L, Zhao D, Wang Y, et al. Focal adhesion kinase (FAK) inhibitor‐defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network[J]. Molecular carcinogenesis, 2021, 60(2): 113-124.
[6]. Sun T, Zhang K, Pangeni R P, et al. G9a promotes invasion and metastasis of non–small cell lung cancer through enhancing focal adhesion kinase activation via NF-κB signaling pathway[J]. Molecular Cancer Research, 2021, 19(3): 429-440.
[7]. Yoshimura A, Horinaka M, Yaoi T, et al. Epithelial-mesenchymal transition status is a remarkable biomarker for the combination treatment with avutometinib and defactinib in KRAS-mutated non-small cell lung cancer[J]. British Journal of Cancer, 2024, 131(2): 361-371.
[8]. Liu J, Xue L, Xu X, et al. FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer[J]. Experimental Cell Research, 2021, 408(2): 112868.
Defactinib hydrochloride是一种小分子激酶抑制剂，可选择性抑制FAK和Pyk2 [1]。Defactinib hydrochloride可抑制FAK自身磷酸化（例如，在Tyr397位点），并阻断整合素介导的下游RAS/MEK/ERK和PI3K/Akt信号通路，从而抑制肿瘤细胞增殖、迁移、存活和血管生成 [2-3]。Defactinib hydrochloride常用于治疗复发性KRAS突变型低级别浆液性卵巢癌 [4]。
在食管鳞状细胞癌中，Defactinib hydrochloride（0-25μM；72h）显著抑制肿瘤细胞生长 [5]。在A549细胞中，Defactinib hydrochloride（1μM；48h）可部分消除G9a增强的细胞侵袭性 [6]。
在NCI-H358细胞异种移植瘤小鼠模型中，Defactinib hydrochloride（10mg/kg；ig；28d）单药治疗可抑制肿瘤生长 [7]。在A427细胞异种移植瘤小鼠模型中，Defactinib hydrochloride（10mg/kg；ip；21d）可抑制肿瘤生长 [8]。