Ashadul Sk Md, K Hemalatha, Matada Gurubasavaraja Swamy Purawarga, Pal Rohit, B V Manjushree, Mounika S, E Haripriya, M P Viji, D Anjan
Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru 560107, Karnataka, India.
Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru 560107, Karnataka, India.
Bioorg Chem. 2025 Jan;154:108011. doi: 10.1016/j.bioorg.2024.108011. Epub 2024 Nov 29.
The phospatidylinositol-3 kinase (PI3K) pathway is a critical intracellular signalling mechanism that is changed or amplified in a variety of cancers, including breast, gastric, ovarian, colorectal, prostate, glioma, and endometrial. PI3K signalling is important for cancer cell survival, angiogenesis, and metastasis, making it a promising therapeutic target. The PI3K kinases in their different isoforms, namely α, β, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for the therapeutic failure of current therapeutics. There are several current and completed clinical trials using PI3K inhibitors (pan, isoform-specific, and dual PI3K/mTOR) to develop effective PI3K inhibitors capable of overcoming resistance to existing drugs. However, the bulk of these inhibitors have had their indications revoked or voluntarily withdrawn due to concerns about their harmful consequences. Several inhibitors containing medicinally privileged scaffolds like thiazole, triazine, benzimidazole, podophyllotoxin, pyridine, quinazoline, thieno-triazole, pyrimidine, triazole, benzofuran, imidazo-pyridazine, oxazole, coumarin, and azepine derivatives have been explored to target the PI3K pathway and/or a specific isoform in the current overview. This article reviews the structure, biological activities, and clinical status of PI3K inhibitors. It focuses on the development techniques, docking insight, and structure-activity connections of PI3K-based inhibitors. The findings provide useful insights and future approaches for the development of promising PI3K-based inhibitors.
磷脂酰肌醇-3激酶（PI3K）信号通路是一种关键的细胞内信号传导机制，在包括乳腺癌、胃癌、卵巢癌、结直肠癌、前列腺癌、神经胶质瘤和子宫内膜癌在内的多种癌症中发生改变或扩增。PI3K信号传导对癌细胞的存活、血管生成和转移至关重要，使其成为一个有前景的治疗靶点。PI3K激酶有不同的亚型，即α、β、δ和γ，分别由PIK3CA、PIK3CB、PIK3CD和PIK3CG基因编码。特定的基因突变或蛋白质的过表达是导致当前治疗方法治疗失败的原因。目前有几项正在进行和已经完成的临床试验，使用PI3K抑制剂（泛PI3K抑制剂、亚型特异性抑制剂和双PI3K/mTOR抑制剂）来开发能够克服对现有药物耐药性的有效PI3K抑制剂。然而，由于担心其有害后果，这些抑制剂中的大部分已被撤销适应症或自愿撤回。在当前的综述中，已经探索了几种含有噻唑、三嗪、苯并咪唑、鬼臼毒素、吡啶、喹唑啉、噻吩并三唑、嘧啶、三唑、苯并呋喃、咪唑并哒嗪、恶唑、香豆素和氮杂环庚烷衍生物等具有药物特权骨架的抑制剂，以靶向PI3K信号通路和/或特定亚型。本文综述了PI3K抑制剂的结构、生物学活性和临床状况。它重点关注基于PI3K的抑制剂的开发技术、对接见解和构效关系。这些发现为开发有前景的基于PI3K的抑制剂提供了有用的见解和未来方法。
