Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, United States.
Department of Chemistry and Physics, Santa Rosa Junior College, Santa Rosa, CA, United States.
Curr Top Med Chem. 2020;20(10):883-900. doi: 10.2174/1568026620666200224101808.
Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.
癌症是一种从古至今一直困扰人类的毁灭性疾病。经过几十年的缓慢研究进展、有前途的药物开发和新靶点的确定，1972 年发起了抗癌战争。PI3K/Akt 途径是一种调节细胞生长的信号通路，在许多人类癌症中过度激活。研究表明，Akt 抑制剂降低 Akt 活性与肿瘤细胞增殖减少有关。已经有几种有前途的候选药物被研究过，包括但不限于 ipatasertib（RG7440），1；afuresertib（GSK2110183），2；uprosertib（GSK2141795），3；capivasertib（AZD5363），4；据报道，这些药物与 ATP 活性位点结合并抑制 Akt 活性，从而对人类癌细胞发挥细胞毒性和抗增殖作用。对于本综述中讨论的大多数化合物，来自各种癌症的临床前研究数据表明，涉及 Akt 信号过度激活的机制基础。变构抑制剂也已知可以改变激酶的活性。Perifosine（KRX-0401），5，一种烷基磷脂，是第一个进入临床开发的变构 Akt 抑制剂，其机制特征是作为一种 PH 结构域依赖性抑制剂，与 ATP 非竞争性。这导致 Akt 酶和细胞活性降低。其他具有类似作用机制的小分子（MK-2206，6，PHT-427，Akti-1/2）抑制剂通过抑制 Akt 膜定位和随后的激活来抑制 Akt 活性，从而改变 Akt 活性，从而抑制 Akt 活性。细胞生长介导的 Akt 活性。已经鉴定出一种 Akt 抑制剂 solenopsin。通过药效团建模、基于能量的计算和性质预测，已经出现了一些有前途的 solenopsin 衍生物。
