Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity,Journal of Medicinal Chemistry

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Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-08-10 , DOI: 10.1021/acs.jmedchem.1c00815
Jinxin Che ₁ , Xiaoyang Dai ₂ , Jian Gao ₁ , Haichao Sheng ₁ , Wenhu Zhan ₁ , Yang Lu ₁ , Dan Li ₁ , Zizheng Gao ₃ , Zegao Jin ₁ , Binhui Chen ₁ , Peihua Luo ₃ , Bo Yang _{1,

3} , Yongzhou Hu ₁ , Qiaojun He _{1,

2,

3,

4,

5} , Qinjie Weng _{2,

3,

4} , Xiaowu Dong _{1,

4,

5}

Affiliation

Rash is one of the primary dose-limiting toxicities of Akt (protein kinase B) inhibitors in clinical trials. Here, we demonstrate the inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis, which promotes us to search for new selective Akt inhibitors with an improved cutaneous safety property. According to our previous research, compound 2 is selected for further optimization for overcoming the disadvantages of compound 1, including high Akt2 inhibition and high toxicity against HaCaT keratinocytes. The dihedral angle-based design and molecular dynamics simulation lead to the identification of Hu7691 (B5) that achieves a 24-fold selectivity between Akt1 and Akt2. Hu7691 exhibits low activity in inducing HaCaT apoptosis, promising kinase selectivity, and excellent anticancer cell proliferation potencies. Based on the superior results of safety property, pharmacokinetic profile, and in vivo efficacy, the National Medical Products Administration (NMPA) approved the investigational new drug (IND) application of Hu7691.

中文翻译：

发现 N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-2-氟-4-(1-甲基-1H-吡唑-5-基)苯甲酰胺 (Hu7691) ，一种有效的选择性 Akt 抑制剂，可降低皮肤毒性

皮疹是临床试验中 Akt（蛋白激酶 B）抑制剂的主要剂量限制性毒性之一。在这里，我们证明 Akt2 同工酶的抑制可能是角质形成细胞凋亡的驱动因素，这促使我们寻找具有改善皮肤安全性的新型选择性 Akt 抑制剂。根据我们前期的研究，选择化合物2进行进一步优化，以克服化合物1的缺点，包括高Akt2抑制作用和对HaCaT角质形成细胞的高毒性。基于二面角的设计和分子动力学模拟鉴定出Hu7691 ( B5 )，其在 Akt1 和 Akt2 之间实现了 24 倍的选择性。 Hu7691在诱导 HaCaT 细胞凋亡方面表现出低活性，具有良好的激酶选择性和出色的抗癌细胞增殖功效。基于Hu7691优异的安全性、药代动力学特征和体内疗效，国家药品监督管理局（NMPA）批准了Hu7691的新药临床试验（IND）申请。

更新日期：2021-08-26

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