纤维母细胞生长因子受体(FGFR)的作用,酪氨酸蛋白激酶抑制剂治疗癌症包括膀胱。

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纤维母细胞生长因子受体(FGFR)的作用,酪氨酸蛋白激酶抑制剂治疗癌症包括膀胱。

药物杂志》2020年1月,151:104567。doi: 10.1016 / j.phrs.2019.104567。Epub 2019年11月23日。

PubMed ID

31770593 (在PubMed

]

文摘

人类成纤维细胞生长因子家族由22个因素和5跨膜受体。十八岁的22个因素,分泌而专门细胞内的四个功能。纤维母细胞生长因子受体4 (FGFRs)拥有细胞内酪氨酸蛋白激酶活性虽然第五(FGFRL1)有一个很短的105 -残留细胞内non-enzymatic组件。FGFR蛋白激酶结构域由一个bi-lobed结构类似于其他蛋白激酶。FGFR基因的改变发生在各种各样的癌症包括膀胱、乳腺癌、卵巢癌、前列腺癌、子宫内膜、肺、胃。绝大多数(66%)的FGFR基因改变涉及基因扩增,其次是变异(26%),和重组产生融合蛋白(8%)。Erdafitinib是第一个口服有效FGFR拮抗剂FDA批准的(2019)治疗晚期癌症,膀胱。磷酸FGF23抑制肾近端小管的重吸收;磷酸FGF23封锁允许再吸收发生并导致血清磷水平升高。Erdafitinib和其他一些,但不是全部,FGFR拮抗剂产生高磷血症。 Erdafitinib binds to an inactive DGF-Din conformation of FGFR1 and is classified as a type I(1/2) inhibitor. Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I(1/2) inhibitors. The inactive conformations contain an autoinhibitory brake that is made up of three main residues: an asparagine (N) within the alphaC-beta4 back loop, a glutamate (E) corresponding to the second hinge residue, and a lysine (K) in the beta8-strand (the NEK triad). PDGFRalpha/beta, Kit, CSF1R, VEGFR1/2/3, Flt3, Tek, and Tie protein kinases are also regulated by a similar autoinhibitory brake mechanism. Ponatinib binds to FGFR4 in a DFG-Dout conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, fisogatinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures. All of the aforementioned FGFR antagonists are orally effective. The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms.

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Pemigatinib