Pillpe-Meza Raysa Magali, Gouveia Wesley Leandro, Barbosa Gisele, Fraga Carlos A M, Barreiro Eliezer J, Lima Lidia Moreira
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
Pharmaceuticals (Basel). 2024 Mar 18;17(3):389. doi: 10.3390/ph17030389.
Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC = 23 µM), human leukaemia cell line CCRF-CEM (IC = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC = 5.44 µM), low absorption by parallel artificial membrane permeability-gastrointestinal tract (PAMPA-GIT) and low permeation by parallel artificial membrane permeability-blood-brain barrier (BBB) (PAMPA-BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC values on MOLT-4 and CCRF-CEM cells.
组蛋白去乙酰化酶（HDAC - 6）的异常表达和磷脂酰肌醇3 - 激酶（PI3K）信号通路的失调是癌症中常见的畸变。LASSBio - 2208，先前已被描述为一种在纳摩尔范围内对HDAC - 6和PI3Kα具有双重抑制作用的抑制剂，并且在抑制HDAC - 6方面的效力是其三倍。在本文中，我们描述了LASSBio - 2208对不同肿瘤细胞系的细胞毒性和抗增殖效力、其与PI3K和HDAC - 6抑制剂联合使用时可能的协同作用，以及其体外药物代谢和药代动力学（DMPK）特征。我们的研究表明，LASSBio - 2208对乳腺癌细胞系MCF - 7（IC = 23 µM）、人白血病细胞系CCRF - CEM（IC = 8.54 µM）和T淋巴母细胞系MOLT - 4（IC = 7.15 µM）具有中等细胞毒性效力，对人外周血单个核细胞（hPBMC）无细胞毒性作用。此外，它对MCF - 7细胞具有良好的抗增殖作用（IC = 5.44 µM），通过平行人工膜通透性 - 胃肠道（PAMPA - GIT）的吸收低，通过平行人工膜通透性 - 血脑屏障（BBB）（PAMPA - BBB）的渗透低，在大鼠血浆中表现出高代谢稳定性。此外，当LASSBio - 2208与吉妥利西布和图巴他汀A联合使用时，使用对应于它们在MOLT - 4和CCRF - CEM细胞上的CC值的浓度，表现出协同作用。
