ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Curr Med Chem. 2013;20(24):2991-3010. doi: 10.2174/09298673113209990124.
Nowadays, cancer treatment is moving away from conventional cytotoxic drugs to target-based agents. This is primarily attributed to some remarkable leaps made in deciphering the tumor-relevant signaling pathways. Among them, PI3K/Akt/mTOR cascade presently elicits a substantial amount of pharmaceutical interests owing to its intimate role in tumor initiation and progression. Additionally, its medicinal potential lies in some protein kinases along the cascade, embracing PI3K, Akt and mTOR, which regulate crucial cellular activities. During the pursuit of PI3K axis inhibitors, medicinal chemistry efforts have diverged into three separate directions for addressing the issues associated with pioneering PI3K axis inhibitors, including poor pharmacokinetic (PK) profiles, low kinase specificity and lack of multiple inhibitory activities. Distinguished from other reviews in the literature, this article will outline these issues in sequence and give an account of recent medicinal chemistry efforts along with updated strides in surmounting them. Particularly, some candidates developed upon these efforts will be highlighted for their design rationale, preclinical performance or clinical status. Rather than merely focus on stunning breakthroughs, the review will critically remind us of the underlying challenges in developing PI3K axis modulators to direct the future research in this field.
如今，癌症治疗正从传统的细胞毒性药物转向基于靶点的药物。这主要归因于在破译肿瘤相关信号通路方面取得了一些显著的进展。其中，PI3K/Akt/mTOR 级联反应因其在肿瘤发生和进展中的密切作用，目前引起了大量的药物研究兴趣。此外，其药用潜力在于级联反应中的一些蛋白激酶，包括 PI3K、Akt 和 mTOR，它们调节着关键的细胞活动。在寻找 PI3K 轴抑制剂的过程中，药物化学研究已经朝着三个不同的方向发展，以解决与开创性的 PI3K 轴抑制剂相关的问题，包括较差的药代动力学（PK）特征、低激酶特异性和缺乏多种抑制活性。与文献中的其他综述不同，本文将依次概述这些问题，并介绍最近药物化学方面的研究进展以及克服这些问题的最新进展。特别是，将重点介绍基于这些研究进展的一些候选药物，以说明其设计原理、临床前表现或临床状况。该综述不仅关注令人瞩目的突破，还批判性地提醒我们，在开发 PI3K 轴调节剂方面仍然存在挑战，这将指导该领域未来的研究。
