Defactinib hydrochlorideは小分子キナーゼ阻害剤であり、FAKとPyk2を選択的に阻害する[1]。Defactinib hydrochlorideはFAK自己リン酸化（例えばTyr397で）を阻害し、インテグリン媒介の下流RAS/MEK/ERKとPI3K/Aktシグナル伝達経路を遮断し、よって腫瘍細胞の増殖、遊離、生存率と血管新生を阻害する[2-3]。Defactinib hydrochlorideは、よく再発性KRAS変異低悪性度漿液性卵巣癌の治療に使われる[4]。
食道扁平上皮癌で、Defactinib hydrochloride (0-25μM；72時間)は、腫瘍細胞の成長を著しく阻害した[5]。A549細胞で、Defactinib hydrochloride (1μM；48時間)は細胞でG9a増強の侵入を部分的に消せる[6]。
NCI-H358細胞異種移植腫瘍マウスモデルで、Defactinib hydrochloride (10mg/kg；ig；28日間)の単独治療は、腫瘍成長を阻害する[7]。A427細胞異種移植腫瘍マウスモデルで、Defactinib hydrochloride (10mg/kg；腹腔内注射；21日間)は腫瘍の成長を阻害する[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.