School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
ChemMedChem. 2019 Feb 19;14(4):494-500. doi: 10.1002/cmdc.201800719. Epub 2019 Jan 14.
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.
1-[(3S)-3-[4-氨基-3-[2-(3,5-二甲氧基苯基)乙炔基]-1H-吡唑并[3,4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮（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，目前正在携带 FGFR 异常的已确诊晚期转移性实体瘤患者中进行 I/II 期临床试验。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。我们的质谱实验描绘了形成共价复合物的异常快速化学反应。这种反应性的结构基础通过一系列三个 X 射线晶体结构揭示：游离配体结构、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 的最显著反应性特征是其固有能力对 FGFR P 环进行构象采样。在设计新型共价 FGFR 抑制剂时，这种现象提供了一种有吸引力的策略，需要将丙烯酰胺基团适当地定位，类似于 TAS-120。
