Thornton Adrian, Komati Rajesh, Kim Hogyoung, Myers Jamiah, Petty Kymmia, Sam Rion, Johnson-Henderson Elijah, Reese Keshunna, Tran Linh, Sridhar Vaniyambadi, Williams Christopher, Sridhar Jayalakshmi
Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, United States.
Department of Chemistry, Nicholls State University, Thibodaux, LA, United States.
Front Mol Biosci. 2024 Dec 19;11:1481912. doi: 10.3389/fmolb.2024.1481912. eCollection 2024.
Many breast cancer therapeutics target the PI3K/AKT/mTOR oncogenic pathway. Development of resistance to the therapeutics targeting this pathway is a frequent occurrence. Therapeutics targeting p70S6K1, a downstream member of this pathway, have recently gained importance due to its critical role in all types of breast cancer and its status as a prognostic marker. We have developed a new class of p70S6K1 inhibitors that show growth inhibition of MCF7 breast cancer cells.
A series of 6-amido-4-aminoisoindolyn-1,3-dione compounds was developed against p70S6K1 using docking, computational modeling tools, and synthesis of the designed compounds. The p70S6K1 inhibition potency of the compounds was investigated in an initial high-throughput screening followed by IC determination for the most active ones. The best compounds were subjected to proliferation assays on MCF7 breast cancer cells. The targeting of p70S6K1 by the compounds was confirmed by studying the phosphorylation status of downstream protein rpS6.
In this study, we have identified a new class of compounds as p70S6K1 inhibitors that function as growth inhibitors of MCF7 breast cancer cells. The structural features imparting p70S6K1 inhibition potency to the compounds have been mapped. Our studies indicate that substitutions on the phenacetyl group residing in the cleft A of the protein do not contribute to the inhibition potency. Three compounds (, and ) have been identified to have sub-micromolar inhibition potency for p70S6K1. These compounds also exhibited growth inhibition of MCF7 cells by 40%-60% in the presence of estradiol.
许多乳腺癌治疗药物靶向PI3K/AKT/mTOR致癌途径。对靶向该途径的治疗药物产生耐药性的情况屡见不鲜。靶向p70S6K1（该途径的下游成员）的治疗药物最近变得愈发重要，因为它在所有类型的乳腺癌中都起着关键作用，并且是一种预后标志物。我们已经开发出一类新型的p70S6K1抑制剂，其对MCF7乳腺癌细胞具有生长抑制作用。
利用对接、计算建模工具以及设计化合物的合成，开发了一系列针对p70S6K1的6-酰胺基-4-氨基异吲哚啉-1,3-二酮化合物。在初步的高通量筛选中研究了这些化合物对p70S6K1的抑制效力，随后对活性最高的化合物进行IC测定。对最佳化合物进行MCF7乳腺癌细胞的增殖测定。通过研究下游蛋白rpS6的磷酸化状态，证实了这些化合物对p70S6K1的靶向作用。
在本研究中，我们鉴定出一类新型化合物作为p70S6K1抑制剂，其作为MCF7乳腺癌细胞的生长抑制剂发挥作用。已经确定了赋予这些化合物p70S6K1抑制效力的结构特征。我们的研究表明，位于蛋白质A裂隙中的苯乙酰基上的取代对抑制效力没有贡献。已鉴定出三种化合物（、和）对p70S6K1具有亚微摩尔抑制效力。在存在雌二醇的情况下，这些化合物还使MCF7细胞的生长受到40%-60%的抑制。
