Holmes Secondra, Jain Prashi, Rodriguez Kenneth Guzman, Williams Jade, Yu Zhifeng, Cerda-Smith Christian, Samuel Errol L G, Campbell James, Hakenjos John Michael, Monsivais Diana, Li Feng, Chamakuri Srinivas, Matzuk Martin M, Santini Conrad, MacKenzie Kevin R, Young Damian W
Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States.
Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
ACS Med Chem Lett. 2024 Jan 2;15(1):107-115. doi: 10.1021/acsmedchemlett.3c00464. eCollection 2024 Jan 11.
The bromodomain inhibitor (+)-JQ1 is a highly validated chemical probe; however, it exhibits poor pharmacokinetics. To guide efforts toward improving its pharmacological properties, we identified the (+)-JQ1 primary metabolite using chemical catalysis methods. Treatment of (+)-JQ1 with tetrabutylammonium decatungstate under photochemical conditions resulted in selective formation of an aldehyde at the 2-position of the thiophene ring [(+)-JQ1-CHO], which was further reduced to the 2-hydroxymethyl analog [(+)-JQ1-OH]. Comparative LC/MS analysis of (+)-JQ1-OH to the product obtained from liver microsomes suggested (+)-JQ1-OH as the major metabolite of (+)-JQ1. The 2-thienyl position was then substituted to generate a trideuterated (-CD, (+)-JQ1-D) analog having half-lives that were 1.8- and 2.8-fold longer in mouse and human liver microsomes, respectively. This result unambiguously confirmed (+)-JQ1-OH as the major metabolite of (+)-JQ1. These studies demonstrate an efficient process for studying drug metabolism and identifying the metabolic soft spots of bioactive compounds.
溴结构域抑制剂(+)-JQ1是一种经过高度验证的化学探针；然而，它的药代动力学较差。为了指导改善其药理性质的研究工作，我们使用化学催化方法鉴定了(+)-JQ1的主要代谢产物。在光化学条件下，用十钨酸四丁铵处理(+)-JQ1，导致在噻吩环的2位选择性形成醛[(+)-JQ1-CHO]，其进一步还原为2-羟甲基类似物[(+)-JQ1-OH]。对(+)-JQ1-OH与从肝微粒体获得的产物进行的比较液相色谱/质谱分析表明，(+)-JQ1-OH是(+)-JQ1的主要代谢产物。然后对2-噻吩基进行取代，生成一种三氘代(-CD，(+)-JQ1-D)类似物，其在小鼠和人肝微粒体中的半衰期分别延长了1.8倍和2.8倍。这一结果明确证实(+)-JQ1-OH是(+)-JQ1的主要代谢产物。这些研究证明了一种研究药物代谢和鉴定生物活性化合物代谢薄弱点的有效方法。
