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Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-23 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01714 Haiyan Yang 1 , Lohitha Rao Chennamaneni 2 , Melvyn Wai Tuck Ho 1 , Shi Hua Ang 1 , Eldwin Sum Wai Tan 1 , Duraiswamy Athisayamani Jeyaraj 1 , Yoon Sheng Yeap 1 , Boping Liu 1 , Esther Hq Ong 1 , Joma Kanikadu Joy 1 , John Liang Kuan Wee 1 , Perlyn Kwek 1 , Priya Retna 1 , Nurul Dinie 1 , Thuy Thi Hanh Nguyen 1 , Shi Jing Tai 1 , Vithya Manoharan 1 , Vishal Pendharkar 1 , Choon Bing Low 1 , Yun Shan Chew 1 , Susmitha Vuddagiri 1 , Kanda Sangthongpitag 1 , Meng Ling Choong 1 , May Ann Lee 1 , Srinivasaraghavan Kannan 3 , Chandra S. Verma 3, 4, 5 , Anders Poulsen 1 , Sharon Lim 6 , Charles Chuah 6 , Tiong Sin Ong 6, 7 , Jeffrey Hill 1 , Alex Matter 1 , Kassoum Nacro 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-23 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01714 Haiyan Yang 1 , Lohitha Rao Chennamaneni 2 , Melvyn Wai Tuck Ho 1 , Shi Hua Ang 1 , Eldwin Sum Wai Tan 1 , Duraiswamy Athisayamani Jeyaraj 1 , Yoon Sheng Yeap 1 , Boping Liu 1 , Esther Hq Ong 1 , Joma Kanikadu Joy 1 , John Liang Kuan Wee 1 , Perlyn Kwek 1 , Priya Retna 1 , Nurul Dinie 1 , Thuy Thi Hanh Nguyen 1 , Shi Jing Tai 1 , Vithya Manoharan 1 , Vishal Pendharkar 1 , Choon Bing Low 1 , Yun Shan Chew 1 , Susmitha Vuddagiri 1 , Kanda Sangthongpitag 1 , Meng Ling Choong 1 , May Ann Lee 1 , Srinivasaraghavan Kannan 3 , Chandra S. Verma 3, 4, 5 , Anders Poulsen 1 , Sharon Lim 6 , Charles Chuah 6 , Tiong Sin Ong 6, 7 , Jeffrey Hill 1 , Alex Matter 1 , Kassoum Nacro 1
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Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure–activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.
中文翻译：
选择性丝裂素活化蛋白激酶相互作用激酶1和2抑制剂治疗高炉危机白血病的优化。
慢性粒细胞白血病（CML）是由bcr-abl1引起的骨髓增生性疾病，bcr-abl1是一种组成型活性的酪氨酸激酶融合基因，负责白血病干细胞（LSCs）的异常增殖。抑制BCR-ABL1激酶活性可为CML患者提供长期缓解。但是，对于其中的一部分，BCR-ABL1抑制将无法有效治疗该疾病，并且CML将发展为爆炸危险（BC）CML，预后较差。BC-CML通常与过量的磷酸化真核翻译起始因子4E（eIF4E）有关，这使LSC能够通过自我更新而增殖，而不受BCR-ABL1抑制。体内，eIF4E在Ser209上仅被MNK1 / 2磷酸化。因此，MNK1 / 2的选择性抑制剂应降低磷酸化eIF4E的水平并使LSC对BCR-ABL1抑制重新敏感，从而阻碍BC LSC的增殖。我们在此报告一种选择性的结构-活性关系和药代动力学性质MNK1 / 2抑制剂临床候选，ETC-206，其在与达沙替尼防止BC-CML LSC自我更新的组合在体外和增强达沙替尼的抗肿瘤活性在体内。
更新日期：2018-04-23
中文翻译：
选择性丝裂素活化蛋白激酶相互作用激酶1和2抑制剂治疗高炉危机白血病的优化。
慢性粒细胞白血病（CML）是由bcr-abl1引起的骨髓增生性疾病，bcr-abl1是一种组成型活性的酪氨酸激酶融合基因，负责白血病干细胞（LSCs）的异常增殖。抑制BCR-ABL1激酶活性可为CML患者提供长期缓解。但是，对于其中的一部分，BCR-ABL1抑制将无法有效治疗该疾病，并且CML将发展为爆炸危险（BC）CML，预后较差。BC-CML通常与过量的磷酸化真核翻译起始因子4E（eIF4E）有关，这使LSC能够通过自我更新而增殖，而不受BCR-ABL1抑制。体内，eIF4E在Ser209上仅被MNK1 / 2磷酸化。因此，MNK1 / 2的选择性抑制剂应降低磷酸化eIF4E的水平并使LSC对BCR-ABL1抑制重新敏感，从而阻碍BC LSC的增殖。我们在此报告一种选择性的结构-活性关系和药代动力学性质MNK1 / 2抑制剂临床候选，ETC-206，其在与达沙替尼防止BC-CML LSC自我更新的组合在体外和增强达沙替尼的抗肿瘤活性在体内。
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