Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of the Chinese Academy of Sciences, Beijing 100049, China.
J Med Chem. 2024 Aug 22;67(16):14277-14291. doi: 10.1021/acs.jmedchem.4c01104. Epub 2024 Jul 29.
Proteolysis-targeting chimeras (PROTACs) have emerged as potentially effective therapeutic medicines, but their high molecular weight and poor solubility directly impact their oral bioavailability. This work synthesized C-labeled bavdegalutamide (ARV-110) as a model compound of PROTACs to evaluate its ADME features. Compared with targeted antitumor drugs, the use of food increased oral bioavailability of ARV-110 in rats from 10.75% to 20.97%, which is still undesirable. However, the therapeutic effect of ARV-110 at a low dose was much better than that of enzalutamide, demonstrating the specific catalytic medicinal properties of PROTACs. Moreover, the specific distribution of ARV-110 in subcutaneous prostate tumors was determined by quantitative whole-body autoradiography (QWBA). Notably, the specificity and activity of PROTACs take precedence over their oral absorption, and high oral bioavailability is not necessary to produce excellent therapeutic effects. This work presents a roadmap for developing future PROTAC medications from a radioactive drug metabolism and pharmacokinetics (DMPK) perspective.
蛋白水解靶向嵌合体（PROTACs）已成为一种有潜力的有效治疗药物，但它们的高分子量和较差的溶解度直接影响其口服生物利用度。本工作合成了 C 标记的巴夫达鲁胺（ARV-110）作为 PROTACs 的模型化合物，以评估其 ADME 特征。与靶向抗肿瘤药物相比，在大鼠中使用食物将 ARV-110 的口服生物利用度从 10.75%提高到 20.97%，但仍不理想。然而，ARV-110 在低剂量下的治疗效果明显优于恩扎鲁胺，这表明了 PROTACs 的特定催化治疗特性。此外，通过定量全身放射自显影（QWBA）确定了 ARV-110 在皮下前列腺肿瘤中的特异性分布。值得注意的是，PROTACs 的特异性和活性优先于其口服吸收，并且产生优异的治疗效果并不需要高口服生物利用度。本工作从放射性药物代谢和药代动力学（DMPK）的角度为开发未来的 PROTAC 药物提供了路线图。
