Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure−activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC₅₀ = 0.007 μM) as well as its crystal structure in complex with the methylated Plk1₃₆₋₃₄₅ construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC₅₀ values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.

中文翻译：

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鉴定 4,5-二氢-1H-吡唑并[4,3-h]喹唑啉衍生物作为一类新型口服选择性 Polo 样激酶 1 抑制剂


Polo 样激酶 1 (Plk1) 是有丝分裂进展的基本调节因子，其过度表达通常与肿瘤发生相关，因此被认为是治疗增殖性疾病的一个有吸引力的治疗靶点。在这里，我们讨论了 4,5-二氢-1 H -吡唑并[4,3- h ]喹唑啉类化合物的构效关系，这些化合物是从高通量筛选 (HTS) 活动中出现的，作为 Plk1 激酶的有效抑制剂。此外，我们描述了49 , 8-{[2-甲氧基-5-(4-甲基哌嗪-1-基)苯基]氨基}-1-甲基-4,5-二氢-1 H-吡唑并[4, 3- h ]quinazoline-3-carboxamide，作为 Plk1 的高效且特异性 ATP 模拟抑制剂 (IC ₅₀ = 0.007 μM) 及其与甲基化 Plk1 ₃₆₋₃₄₅构建体复合的晶体结构。化合物49在针对不同肿瘤细胞系的细胞增殖中具有活性，IC ₅₀值在亚微摩尔范围内，并且在HCT116异种移植模型中具有体内活性，在重复口服给药后显示出82%的肿瘤生长抑制。