Toenjes Sean T, Heydari Bahar S, Albright Samuel T, Hazin Ramsey, Ortiz Maria A, Piedrafita F Javier, Gustafson Jeffrey L
Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States.
ACS Med Chem Lett. 2023 Feb 14;14(3):305-311. doi: 10.1021/acsmedchemlett.2c00523. eCollection 2023 Mar 9.
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 -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.
依鲁替尼是一种共价布鲁顿酪氨酸激酶（BTK）抑制剂，已被批准用于多种肿瘤适应症。依鲁替尼对许多激酶具有显著的脱靶活性，常常导致患者出现不良事件。尽管已经通过强大的药物化学努力研发出了更具选择性的第二代BTK抑制剂，但仍需要新的策略来快速提高激酶抑制剂的选择性。对蛋白质数据银行（PDB）数据的分析表明，依鲁替尼以与依鲁替尼预测的低能量构象范围正交的二面角构象结合BTK。合成了一系列基态构象向正交性转变的类似物，从而发现了一种含有两个甲基的类似物，其对BTK的选择性显著提高。这项工作表明，围绕潜在的阻转异构轴进行构象控制代表了一种快速调整化合物对给定靶点选择性的策略。
