The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor
The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor
复制标题
DOI：
10.1158/1535-7163.mct-14-0248
复制
发表时间：
2014-11-01
影响因子：
5.7
通讯作者：
Ishii, Nobuya
中科院分区：
文献类型：
--
作者：
Nakanishi, Yoshito;Akiyama, Nukinori;Ishii, Nobuya
FGF 受体 (FGFR) 是一种酪氨酸激酶，在部分肿瘤中通过基因扩增、点突变或染色体易位/重排等遗传改变而被组成型激活。最近，可以抑制 FGFR 家族以及 VEGF 受体 (VEGFR) 或血小板源性生长因子受体 (PDGFR) 家族的小分子抑制剂在 FGFR 基因改变的患者群体中显示出临床益处。然而，为了在此类人群中获得更有效和更持久的活性，仍然需要选择性 FGFR 抑制剂。在此，我们报告了 CH5183284/Debio 1347 的鉴定，这是一种选择性口服 FGFR1、FGFR2 和 FGFR3 抑制剂，具有独特的化学支架。通过与 FGFR1、FGFR2 或 FGFR3 的 ATP 结合位点中的独特残基相互作用，CH5183284/Debio 1347 选择性抑制 FGFR1、FGFR2 和 FGFR3，但不抑制激酶插入域受体 (KDR) 或其他激酶。与其对 FGFR 酶的高选择性一致，CH5183284/Debio 1347 在 327 个癌细胞系和异种移植模型中对具有各种 FGFR 基因改变的癌细胞表现出优先的抗肿瘤活性。由于其独特的结合模式，CH5183284/Debio 1347 可以抑制含有一种类型的看门突变的 FGFR2，这种突变会导致对其他 FGFR 抑制剂的耐药性，并阻止 FGFR2 V564F 驱动的肿瘤生长。 CH5183284/Debio 1347 正在接受临床研究，用于治疗携带 FGFR 基因改变的患者。 (C) 2014 年 AACR。
The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations. (C) 2014 AACR.