TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure
TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure
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DOI：
10.1002/cmdc.201800719
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发表时间：
2019-02-19
期刊：
影响因子：
3.4
通讯作者：
Squire, Christopher J.
中科院分区：
文献类型：
--
作者：
Kalyukina, Maria;Yosaatmadja, Yuliana;Squire, Christopher J.
1-[(3S)-3-[4-氨基-3-[2-（3,5-二甲氧基苯基）乙基]- 1h -pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-丙烯-1- 1-one （TAS-120）是一种不可逆的成纤维细胞生长因子受体（FGFR）家族抑制剂，目前正在进行I/II期临床试验，用于治疗患有FGFR异常的晚期转移性实体肿瘤患者。该抑制剂特异性靶向FGFR酪氨酸激酶结构域的p环，与蛋白质的半胱氨酸侧链形成共价加合物。我们的质谱实验表征了形成共价复合物的异常快速的化学反应。这种反应性的结构基础由三种x射线晶体结构序列揭示：自由配体结构，可逆FGFR1结构和首次报道的不可逆FGFR1加合物结构。我们假设TAS-120最重要的反应性特征是其固有的对FGFR p环进行构象采样的能力。在设计新型共价FGFR抑制剂时，这种现象提出了一种有吸引力的策略，需要适当定位丙烯酰胺基团，类似于TAS-120。
1-[(3S)-3-[4-Amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one (TAS-120) is an irreversible inhibitor of the fibroblast growth factor receptor (FGFR) family, and is currently under phase I/II clinical trials in patients with confirmed advanced metastatic solid tumours harbouring FGFR aberrations. This inhibitor specifically targets the P-loop of the FGFR tyrosine kinase domain, forming a covalent adduct with a cysteine side chain of the protein. Our mass spectrometry experiments characterise an exceptionally fast chemical reaction in forming the covalent complex. The structural basis of this reactivity is revealed by a sequence of three X-ray crystal structures: a free ligand structure, a reversible FGFR1 structure, and the first reported irreversible FGFR1 adduct structure. We hypothesise that the most significant reactivity feature of TAS-120 is its inherent ability to undertake conformational sampling of the FGFR P-loop. In designing novel covalent FGFR inhibitors, such a phenomenon presents an attractive strategy requiring appropriate positioning of an acrylamide group similarly to that of TAS-120.