Tsimafeyeu Ilya, Daeyaert Frits, Joos Jean-Baptiste, Aken Koen V, Ludes-Meyers John, Byakhov Mikhail, Tjulandin Sergei
Ruspharmtech LLC, Griboyedov canal nab. 130 Liter A, off. 202, Saint Petersburg, 190121, Russia.
Med Chem. 2016;12(4):303-17. doi: 10.2174/1573406412666160106154726.
Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a combined molecular modeling and de novo design strategy.
Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program 'SYNOPSIS' to generate high scoring and synthetically accessible compounds.
Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L.
These results provide strong rationale for the evaluation of compound in advanced cancers.
成纤维细胞生长因子（FGF）受体（FGFRs）在肿瘤生长和血管生成中起关键作用。本报告描述了我们使用分子建模和从头设计相结合的策略寻找细胞外结合FGFR抑制剂的过程。
基于受体与其天然配体的晶体结构以及抑制肽的知识，我们开发了一种计算方案，可预测分子与受体细胞外结构域的假定结合。该方案或评分函数与从头合成程序“SYNOPSIS”结合使用，以生成高分且可合成的化合物。
合成了属于3个不同化学类别的8种化合物。其中一种化合物，阿洛法尼布（RPT835），被发现是FGF/FGFR2途径的有效抑制剂。临床前体外数据支持RPT835的变构抑制机制。RPT835强烈抑制表达FGFR2的KATO III胃癌细胞的生长，GI50值为10 nmol/L。
这些结果为在晚期癌症中评估该化合物提供了有力的理论依据。
