Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors,Journal of Medicinal Chemistry

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Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-19 , DOI: 10.1021/acs.jmedchem.4c00411
Joshua Gerninghaus _{1,

2} , Rezart Zhubi _{1,

2} , Andreas Krämer _{1,

2} , Marwah Karim ₃ , Do Hoang Nhu Tran ₃ , Andreas C Joerger _{1,

2} , Christian Schreiber _{1,

2} , Lena M Berger _{1,

2} , Benedict-Tilman Berger _{1,

2} , Theresa A L Ehret _{1,

2} , Lewis Elson _{1,

2} , Christopher Lenz _{1,

2} , Krishna Saxena _{1,

2} , Susanne Müller _{1,

2} , Shirit Einav _{3,

4} , Stefan Knapp _{1,

2} , Thomas Hanke _{1,

2}

Affiliation

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55, a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.

中文翻译：

基于 2-氨基嘧啶的大环化合物的后袋优化可产生有效的 EPHA2/GAK 激酶抑制剂

无环化合物的大环化是提高抑制剂效力和选择性的有力策略。在这里，我们优化了基于 2-氨基嘧啶的大环化合物，以使用这些化合物作为肝配蛋白激酶家族的化学工具。从混杂的大环抑制剂6开始，我们使用一组超过 100 种激酶进行了结构引导的活性关系和选择性研究。 EPHA2 与开发的大环23复合物的晶体结构为通过专门针对后袋进行进一步优化提供了基础，产生了化合物55 ，它是 EPHA2/A4 和 GAK 的有效抑制剂。随后的前袋衍生化导致了令人感兴趣的纤维素选择性谱，与其他肝配蛋白受体激酶家族成员相比，EPHA4 更受青睐。 EPHA2/A4 和 GAK 双重抑制剂55可预防 Huh7 肝细胞的登革热病毒感染。然而，需要进一步研究以确定这是否是化合物特异性效应或目标相关效应。

更新日期：2024-07-19

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