Millan David S, Kayser-Bricker Katherine J, Martin Matthew W, Talbot Adam C, Schiller Shawn E R, Herbertz Torsten, Williams Grace L, Luke George P, Hubbs Stephen, Alvarez Morales Monica A, Cardillo Daniel, Troccolo Paul, Mendes Rachel L, McKinnon Crystal
FORMA Therapeutics Inc., 500 Arsenal Street, Suite 100, Watertown, Massachusetts 02472, United States.
FORMA Therapeutics Inc., 35 Northeast Industrial Road, Branford, Connecticut 06405, United States.
ACS Med Chem Lett. 2017 Jul 14;8(8):847-852. doi: 10.1021/acsmedchemlett.7b00191. eCollection 2017 Aug 10.
A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound , which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).
采用一种基于蛋白质结构的药物设计方法来开发与已知的（+）-JQ1支架类不同的溴结构域BET家族小分子抑制剂。这些研究工作导致鉴定出一系列具有能够与溴结构域结合位点的许多亲和力驱动区域相互作用的结构特征的取代苯并哌嗪。在改善结合亲和力的同时，亲脂性效率是一个指导原则，同时还需具备与口服生物利用度相称的类药物理化性质。从该系列中衍生出工具化合物，其表现出强大的生化和细胞活性，并在小鼠异种移植模型（MV-4-11）中转化为优异的体内活性。
