NUS Graduate School for Integrative Sciences and Engineering, 21 Lower Kent Ridge, University Hall, Tan China Tuan Wing, #04-02, Singapore, 119077, Singapore.
Experimental Drug Development Centre, 10 Biopolis Road, Chromos, #05-01, Singapore, 138670, Singapore.
Angew Chem Int Ed Engl. 2021 Jul 26;60(31):17131-17137. doi: 10.1002/anie.202105383. Epub 2021 Jun 24.
Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABL bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.
靶向共价抑制剂作为已验证的药物重新出现，以克服癌症治疗中的获得性耐药性。在此，我们通过使用羰基硼酸（CBA）弹头，报告了基于结构的 BCR-ABL 抑制剂设计，通过可逆共价靶向催化赖氨酸，提高了对野生型和突变型 ABL 激酶的活性，特别是对带有看门残基突变的 ABL。我们表明，进化上保守的赖氨酸可以被选择性地靶向，这种选择性在很大程度上取决于这类抑制剂中非共价药效团的分子识别，可能是由于弹头的反应性适中。我们报告了第一个共价抑制剂-ABL 激酶结构域复合物的共晶结构，为弹头与催化赖氨酸的相互作用提供了深入了解。我们还使用无标记质谱法在不同的哺乳动物细胞中在蛋白质组范围内评估了我们化合物的非靶标。
