- SMALL MOLECULE STAT PROTEIN DEGRADERS
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The present disclosure provides compounds represented by Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R1a, R1b, R3a, R4, A, E1, E2, M, and Q are as set forth in the specification. Compounds of Formula (I) are STAT protein degraders and thus are useful for the treatment of cancer and other diseases.
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Paragraph 0997
(2021/10/02)
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- SMALL MOLECULE DEGRADERS OF STAT3
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The present disclosure provides compounds represented by Formula I or Formula VIII: wherein R1a, R1b, M, A, E, QA, and QB are as defined in the specification, and the salts and solvates thereof. Compounds of Formula I are degraders of STAT3 or dedraders of STAT3 and STAT1. Compounds of Formula VIII are inhibitors of STAT3. STAT3 degraders and inhibitors are useful for the treatment of cancer and other diseases.
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Paragraph 1345
(2020/10/20)
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- STAT3 PROTEIN DEGRADERS
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The present disclosure provides compounds represented by Formulae I and IV: wherein R1a, R1b, R2a, R2b, A, E, QD, and QE are as defined in the specification, and the salts and solvates thereof. Compounds of Formula I are degraders of STAT3. Compounds of Formula IV are inhibitors of STAT3. STAT3 degraders and inhibitors are useful for the treatment of cancer and other diseases.
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Paragraph 0571; 0572
(2020/10/20)
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- Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein
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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for cancer and other human diseases. Despite 20 years of persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 degrader.
- Zhou, Haibin,Bai, Longchuan,Xu, Renqi,Zhao, Yujun,Chen, Jianyong,McEachern, Donna,Chinnaswamy, Krishnapriya,Wen, Bo,Dai, Lipeng,Kumar, Praveen,Yang, Chao-Yie,Liu, Zhaomin,Wang, Mi,Liu, Liu,Meagher, Jennifer L.,Yi, Han,Sun, Duxin,Stuckey, Jeanne A.,Wang, Shaomeng
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p. 11280 - 11300
(2019/12/27)
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- STAT3 INHIBITORS AND THERAPEUTIC METHODS USING THE SAME
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Inhibitors of STAT3 are disclosed. Methods of using the STAT3 inhibitors in the treatment of diseases and conditions wherein inhibition of STAT3 provides a benefit, like cancers, also are disclosed.
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Page/Page column 42
(2010/08/04)
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