Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Department of Vascularsurgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Eur J Med Chem. 2024 Dec 5;279:116906. doi: 10.1016/j.ejmech.2024.116906. Epub 2024 Sep 27.
Akt, a key regulator of cell survival, proliferation, and metabolism, has become a prominent target for treatment of cancer and inflammatory diseases. The journey of small-molecule Akt inhibitors from discovery to the clinic has faced numerous challenges, with a significant emphasis on optimization throughout the development process. Early discovery efforts identified various classes of inhibitors, including ATP-competitive and allosteric modulators. However, during preclinical and clinical development, several issues arose, including poor specificity, limited bioavailability, and toxicity. Optimization efforts have been central to overcoming these hurdles. Researchers focused on enhancing the selectivity of inhibitors to target Akt isoforms more precisely, reducing off-target effects, and improving pharmacokinetic properties to ensure better bioavailability and distribution. Structural modifications and the design of prodrugs have played a crucial role in refining the efficacy and safety profile of these inhibitors. Additionally, efforts have been made to optimize the therapeutic window, balancing effective dosing with minimal adverse effects. The review highlights how these optimization strategies have been key in advancing small-molecule Akt inhibitors toward clinical success and underscores the importance of continued refinement in their development.
Akt 是细胞存活、增殖和代谢的关键调节因子，已成为治疗癌症和炎症性疾病的重要靶点。从小分子 Akt 抑制剂的发现到临床应用，这一过程面临着诸多挑战，在整个开发过程中都非常注重优化。早期的发现工作确定了多种抑制剂类别，包括 ATP 竞争性抑制剂和别构调节剂。然而，在临床前和临床开发过程中，出现了一些问题，包括特异性差、生物利用度有限和毒性。优化工作对于克服这些障碍至关重要。研究人员专注于提高抑制剂的选择性，以更精确地靶向 Akt 同工型，减少脱靶效应，并改善药代动力学特性，以确保更好的生物利用度和分布。结构修饰和前药设计在完善这些抑制剂的疗效和安全性方面发挥了关键作用。此外，还努力优化治疗窗，平衡有效剂量和最小不良反应。该综述强调了这些优化策略在推动小分子 Akt 抑制剂向临床成功方面的重要性，并强调了在其开发过程中持续改进的重要性。
