Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, Egypt.
Eur J Med Chem. 2019 Dec 1;183:111718. doi: 10.1016/j.ejmech.2019.111718. Epub 2019 Sep 20.
Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
磷脂酰肌醇-3 激酶（PI3K）途径是人类恶性肿瘤中最常被激活的致病信号级联之一。PI3K 在多种癌症中发生遗传突变或过度表达，包括卵巢癌、乳腺癌、前列腺癌、胃癌、结直肠癌、胶质母细胞瘤、子宫内膜癌和脑癌。目前仍在进行研究，以寻找更有效和选择性的 PI3K 抑制剂或双重 PI3K 抑制剂来克服对现有抑制剂的耐药性。这篇综述将重点介绍三种具有有效抗肿瘤活性的主要 PI3K 抑制剂：同工型选择性 PI3K 抑制剂、双重泛 Class I PI3K/mTOR 抑制剂和无明显 mTOR 活性的泛 Class I PI3K 抑制剂。同工型选择性 PI3K 抑制剂分为 4 个 IA、IB、II 和 III 类。此外，还将讨论每个类别之间的 SAR 以及生物学活性。此外，还将强调为克服新出现的耐药性而设计新型候选药物的新范围。
