Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies,Journal of Medicinal Chemistry

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Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-23 , DOI: 10.1021/acs.jmedchem.4c00837
Abdusaid Saidahmatov _{1,

2} , Jianan Li ₃ , Shihao Xu _{1,

2} , Xiaobei Hu _{1,

4} , Xiangqian Gao ₃ , Weijuan Kan ₁ , Lixin Gao ₁ , Cong Li ₁ , Yuqiang Shi ₁ , Li Sheng ₁ , Peipei Wang ₁ , Yubo Zhou _{1,

2,

4} , Xuewu Liang _{1,

2} , Jia Li _{1,

2,

3,

4,

5} , Hong Liu _{1,

2}

Affiliation

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC₅₀ values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4–11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4–11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC₅₀ = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4–11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

中文翻译：

发现新型 2-氨基吡啶基和 2-氨基嘧啶基衍生物作为有效的 CDK/HDAC 双重抑制剂，用于治疗难治性实体瘤和血液恶性肿瘤

组蛋白脱乙酰酶 (HDAC) 和细胞周期蛋白依赖性激酶 (CDK) 的共同抑制协同作用，产生增强的抗肿瘤作用，并有可能克服耐药性。在这项工作中，我们发现了一系列新型CDK9/HDACs双重抑制剂。其中，化合物8e被鉴定显示出有效的CDK9和HDAC1抑制活性，IC ₅₀值分别为88.4和168.9 nM，并且表现出对血液和实体瘤细胞的抗增殖能力。同时， 8e对CDK9和HDAC1表现出高选择性，显着诱导MV-4-11细胞凋亡和S细胞周期停滞。此外， 8e具有显着的抗肿瘤效力，在 MV-4-11 异种移植模型中T / C值为 29.98%。有趣的是，还鉴定了一种有效的FLT3/HDAC双重抑制剂9e （FLT3/HDAC1/3 IC ₅₀ = 30.4/52.4/14.7 nM），并发现其在MV-4-11细胞中具有强大的凋亡诱导能力和针对FLT3的有效抗增殖能力突变体转化的 BaF3 细胞。总的来说，我们的工作为具有有效抗癌活性的双重抑制剂提供了有价值的先导化合物。

更新日期：2024-08-23

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