Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.
J Med Chem. 2022 Feb 24;65(4):3173-3192. doi: 10.1021/acs.jmedchem.1c01165. Epub 2022 Feb 15.
Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, , targeting a poorly conserved cysteine in the kinase's hinge region. shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.
单极纺锤体激酶 1（MPS1/TTK）是有丝分裂检查点的关键组成部分，临床上被评估为治疗侵袭性肿瘤（如三阴性乳腺癌）的靶点。虽然较长的药物靶标停留时间被认为在治疗性 MPS1 抑制的情况下是有益的，但尚未报道不可逆的抑制剂。在这里，我们展示了第一个不可逆的共价 MPS1 抑制剂的设计和特性，该抑制剂针对激酶铰链区域中一个保守性较差的半胱氨酸。 对所有具有等效半胱氨酸的蛋白激酶以及更广泛的激酶组均显示出强大的 MPS1 抑制活性和选择性。我们证明了对各种癌细胞系的有效细胞靶标结合和显著的活性。共价结合模式通过质谱和 X 射线晶体结构得到了验证。该 MPS1 共价配体结合能力的证明可能为设计 MPS1 特异性化学探针或药物开辟新途径。
