Controlling Ibrutinib's Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity.
Controlling Ibrutinib's Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity.
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DOI：
10.1021/acsmedchemlett.2c00523
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发表时间：
2023-03-09
影响因子：
4.2
通讯作者：
Gustafson, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Toenjes, Sean T.;Heydari, Bahar S.;Albright, Samuel T.;Hazin, Ramsey;Ortiz, Maria A.;Piedrafita, F. Javier;Gustafson, Jeffrey L.
伊布鲁替尼是一种共价BTK抑制剂，已被批准用于肿瘤学的几种适应症。伊布鲁替尼对许多激酶具有显著的非靶向活性，经常导致患者的不良事件。虽然已经有了强有力的药物化学努力，导致了更具选择性的第二代BTK抑制剂，但仍然需要新的策略来迅速提高激酶抑制剂的选择性。对PDB数据的分析表明，ibrutinib以与ibrutinib预测的低能构象范围垂直的二面体构象结合BTK。合成了一系列基态构象向正交性移动的类似物，发现了一种含有两个邻甲基团的类似物，具有明显提高的BTK选择性。这项工作表明，关于预期的阿托异构体轴的构象控制代表了一种快速编程化合物对给定目标的选择性的策略。
Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib’s predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho-methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound’s selectivity toward a given target.
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影响因子：
5.6
作者：
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通讯作者：
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DOI：
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期刊：
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发表时间：
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影响因子：
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作者：
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DOI：
10.1056/nejmoa1509981
发表时间：
2016-01-28
期刊：
The New England journal of medicine
影响因子：
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作者：
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通讯作者：
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