Cancer Research UK Centre of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
J Med Chem. 2010 Mar 11;53(5):1964-78. doi: 10.1021/jm901509a.
We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.
我们最近报道了一系列新型 BRAF 抑制剂的开发，这些抑制剂基于三方 A-B-C 系统，其特征是具有取代的中央芳核，连接到咪唑[4,5]吡啶-2-酮骨架和取代的脲连接子。在这里，我们提出了一系列新的 BRAF 抑制剂，其中中央苯基环通过间位取代模式与 BRAF 的铰链结合物和底物口袋连接。这个新骨架的优化导致了低纳摩尔抑制剂的开发，这使得可以使用更广泛的连接子和末端 C 环，同时与对位系列相比提高了对 BRAF 酶的选择性。
