Peloton Therapeutics, Inc. , 2330 Inwood Road, Suite 226 , Dallas , Texas 75235 , United States.
J Med Chem. 2018 Nov 8;61(21):9691-9721. doi: 10.1021/acs.jmedchem.8b01196. Epub 2018 Oct 18.
HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π* interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.
缺氧诱导因子-2α（HIF-2α）是 HIF 转录因子家族的成员，是包括透明细胞肾细胞癌（ccRCC）在内的多种癌症中的关键致癌驱动因子。这些癌症的一个显著特征是 HIF-2α 蛋白的过度积累，通常是通过 E3 连接酶 VHL（von Hippel-Lindau）的失活。在此，我们公开了我们的基于结构的药物设计（SBDD）方法，最终确定了 PT2385 作为首个进入临床试验的 HIF-2α 拮抗剂。亮点包括使用假定的 n → π* 相互作用来指导早期类似物设计，对必需的羟基部分进行构象限制，以及羟基附近的氟取代的显著影响。在一系列 PK/PD、疗效、PK 和代谢物分析中，对两个结构类别中的选定化合物进行评估，确定 10i（PT2385，荧光素 EC = 27 nM）为临床候选药物。最后，回顾性晶体学分析描述了实现有效拮抗所需的结构扰动。
