Derazantinib is a novel, ATP competitive, small molecule, multi-kinase inhibitor with IC50 of 1.8nM for FGFR2, and 4.5nM for FGFR1 and 3[1].
Derazantinib rescued the FGF2-mediated growth arrest with EC50 at ~100nM in rat chondrosarcoma (RCS) cells, with no significant toxicity detected for up to 500nM. The concentration range at which Derazantinib significantly suppressed the FGF2 effect was between 70-500nM. Derazantinib inhibits FGF-mediated loss of extracellular matrix and induction of chondrocyte premature senescence. Derazantinib reduced FGFR-driven excessive osteogenic differentiation in mouse mesenchymal micromass cultures and ex vivo calvarial organ cultures[2]. Derazantinib(100μM, 72h) has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between Derazantinib(1μM, 24h/72h) induced G1 cell cycle arrest and subsequent induction of apoptosis[1].
Derazantinib demonstrated efficacy in multiple in vivo xenograft models(NCI-H716 and SNU-16), and was well tolerated at doses up to 75mg/kg(administered orally, a single oral dose)[1]. Derazantinib is active and safe when administered daily for 10-15 days at a dose range of 50-150mg/kg given orally in xenograft models,which were obtained from H1581 lung cancer, MFE296 and SNU16 gastric cancer[3].
References:
[1] Hall T G, Yu Y, Eathiraj S, et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation[J]. PLoS One, 2016, 11(9): e0162594.
[2]Balek L, Gudernova I, Vesela I, et al. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3[J]. Bone, 2017, 105: 57-66.
[3]Chilà R, Hall T, Abbadessa G, et al. Multi-chemotherapeutic schedules containing the pan-FGFR inhibitor ARQ 087 are safe and show antitumor activity in different xenograft models[J]. Translational Oncology, 2017, 10(2): 153-157.
Derazantinib是一种新型的、ATP竞争性的小分子多激酶抑制剂，对FGFR2的 IC50 为 1.8nM，对FGFR1 和FGFR3的IC50 分别为4.5nM[1]。
Derazantinib可挽救大鼠软骨肉瘤（RCS）细胞中FGF2介导的生长停滞，其EC50约为100nM，在高达500nM的浓度下未检测到明显毒性。Derazantinib显著抑制FGF2效应的浓度范围在70-500nM之间。Derazantinib能抑制FGF介导的细胞外基质丢失和软骨细胞过早衰老。在小鼠间充质微团培养和离体颅骨器官培养中，Derazantinib可减少FGFR驱动的过度成骨分化[2]。Derazantinib（100μM，72小时）对由FGFR 失调（包括扩增、融合和突变）驱动的细胞系具有抗增殖活性。对FGFR2蛋白水平高的细胞系进行的细胞周期研究表明，Derazantinib（1μM，24小时/72小时）诱导的G1期细胞周期停滞与随后的凋亡诱导之间存在正相关[1]。
Derazantinib在多种体内异种移植模型（NCI-H716和SNU-16）中显示出疗效，并且在口服剂量高达75mg/kg（单次口服剂量）时耐受性良好[1]。在H1581肺癌、MFE296和SNU16胃癌的异种移植模型中，Derazantinib以50-150mg/kg的剂量口服给药，每日一次，持续10-15天时，具有活性且安全性良好[3]。