State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2024 Sep 12;67(17):15691-15710. doi: 10.1021/acs.jmedchem.4c01304. Epub 2024 Aug 13.
The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound with 38-fold enhanced PP5 selectivity (PP2A/5 IC = 33.8/0.9 μM) and improved drug-like properties (favorable stability and safety, = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor . Importantly, we found the spatial conformational restriction of the indole fragment was responsible for the selectivity of PP5. Thus, activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.
丝氨酸/苏氨酸磷酸酶家族在肿瘤的进展和存活中起着重要作用。由于其高度保守的催化结构域，设计选择性抑制剂具有挑战性。在此，我们通过基于 II 期 PP2A/5 双重靶标抑制剂的合理药物设计，获得了化合物 ，其对 PP5 的选择性提高了 38 倍（PP2A/5 IC = 33.8/0.9 μM），且具有更好的药物特性（良好的稳定性和安全性， = 82.0%）。重要的是，我们发现吲哚片段的空间构象限制是 PP5 选择性的原因。因此， 激活了 p53，并下调了细胞周期蛋白 D1 和 MGMT，在 U87 MG 细胞系中表现出细胞周期阻滞和逆转替莫唑胺（TMZ）耐药的能力。此外， 与 TMZ 的口服给药具有良好的耐受性，能够有效地抑制异种移植模型中的肿瘤生长（TGI = 87.7%）。总之，这些结果表明， 通过选择性抑制 PP5 逆转 TMZ 耐药性， 可能成为一种候选药物。
