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Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-05-09 00:00:00 , DOI: 10.1021/acsmedchemlett.9b00108 Philip A. Harris , Jill M. Marinis , John D. Lich , Scott B. Berger , Anirudh Chirala , Julie A. Cox , Patrick M. Eidam , Joshua N. Finger , Peter J. Gough , Jae U. Jeong , James Kang , Viera Kasparcova , Lara K. Leister , Mukesh K. Mahajan , George Miller , Rakesh Nagilla , Michael T. Ouellette , Michael A. Reilly , Alan R. Rendina , Elizabeth J. Rivera , Helen H. Sun , James H. Thorpe 1 , Rachel D. Totoritis , Wei Wang , Dongling Wu , Daohua Zhang , John Bertin , Robert W. Marquis
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-05-09 00:00:00 , DOI: 10.1021/acsmedchemlett.9b00108 Philip A. Harris , Jill M. Marinis , John D. Lich , Scott B. Berger , Anirudh Chirala , Julie A. Cox , Patrick M. Eidam , Joshua N. Finger , Peter J. Gough , Jae U. Jeong , James Kang , Viera Kasparcova , Lara K. Leister , Mukesh K. Mahajan , George Miller , Rakesh Nagilla , Michael T. Ouellette , Michael A. Reilly , Alan R. Rendina , Elizabeth J. Rivera , Helen H. Sun , James H. Thorpe 1 , Rachel D. Totoritis , Wei Wang , Dongling Wu , Daohua Zhang , John Bertin , Robert W. Marquis
Affiliation
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RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.
中文翻译：
确定用于治疗胰腺癌的RIP1激酶抑制剂临床候选药物（GSK3145095）
RIP1调节细胞死亡和炎症，并被认为在促成多种人类疾病（包括免疫介导的炎性疾病和癌症）中起着重要作用。尽管RIP1激酶的小分子抑制剂已被开发用于炎性疾病和中枢神经系统适应症的临床，但用于肿瘤适应症的RIP1抑制剂尚未有描述。在此，我们报告GSK3145095（化合物6）的发现和概况。化合物6与精致的激酶特异性有效结合RIP1，并在阻止RIP1激酶依赖性细胞应答中具有出色的活性。该抑制剂突出了其作为新型癌症疗法的潜力，还能够在胰腺腺癌器官培养物中促进肿瘤抑制性T细胞表型。化合物6目前正处于针对胰腺腺癌和其他某些实体瘤的1期临床研究中。
更新日期：2019-05-09
中文翻译：
确定用于治疗胰腺癌的RIP1激酶抑制剂临床候选药物（GSK3145095）
RIP1调节细胞死亡和炎症，并被认为在促成多种人类疾病（包括免疫介导的炎性疾病和癌症）中起着重要作用。尽管RIP1激酶的小分子抑制剂已被开发用于炎性疾病和中枢神经系统适应症的临床，但用于肿瘤适应症的RIP1抑制剂尚未有描述。在此，我们报告GSK3145095（化合物6）的发现和概况。化合物6与精致的激酶特异性有效结合RIP1，并在阻止RIP1激酶依赖性细胞应答中具有出色的活性。该抑制剂突出了其作为新型癌症疗法的潜力，还能够在胰腺腺癌器官培养物中促进肿瘤抑制性T细胞表型。化合物6目前正处于针对胰腺腺癌和其他某些实体瘤的1期临床研究中。
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