{"title":"新型高效三重IKZF1/2/3降解剂治疗血液病的发现。","authors":"Ting Wei, Shiyang Sun, Xiaotong Hu, Pengli Wei, Zhiya Fan, Jian Yan, Yalei Wang, Zhenze Qi, Changkai Jia, Yaqiu Mao, Tingting Yang, Xu Cai, Bingkun Li, Zhiyuan Zhao, Min Qiao, Yaxin Zou, Weijie Qin, Xuesong Feng*, Hongzhou Shang*, Pengyun Li*, Zhibing Zheng* and Song Li, ","doi":"10.1021/acs.jmedchem.5c01086","DOIUrl":null,"url":null,"abstract":"<p >Immunomodulatory drugs (IMiDs) are widely utilized therapies in multiple hematological cancers; however, their clinical application is frequently constrained by drug resistance. Here, though screening of diverse cereblon (CRBN) binders, comprehensive structure–activity relationships (SAR) analyses and systematic degradation profiling, <b>MGD-22</b>, a potent IKZF1/2/3 degrader featuring a phthalazinone scaffold, demonstrated nanomolar-range IC<sub>50</sub> potencies across diverse multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL) cancer cells and overcame acquired resistance to pomalidomide. <b>MGD-22</b> selectively induced robust degradation of IKZF1/2/3 in a Cullin-CRBN pathway-dependent manner, with nanomolar DC<sub>50</sub> potency. Furthermore, orally administered <b>MGD-22</b> demonstrated significant tumor growth inhibition with admirable pharmacokinetic properties and displayed s marked synergistic effects with Bruton’s tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitor, respectively, in DLBCL cancer cells. Collectively, these findings establish a rationale for triple-targeted degradation of IKZF1/2/3 and position <b>MGD-22</b> as a promising therapeutic candidate with broader applicability in hematological cancer treatment.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 15","pages":"16237–16259"},"PeriodicalIF":6.8000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Novel Potent Triple IKZF1/2/3 Degraders for the Treatment of Hematological Cancers\",\"authors\":\"Ting Wei, Shiyang Sun, Xiaotong Hu, Pengli Wei, Zhiya Fan, Jian Yan, Yalei Wang, Zhenze Qi, Changkai Jia, Yaqiu Mao, Tingting Yang, Xu Cai, Bingkun Li, Zhiyuan Zhao, Min Qiao, Yaxin Zou, Weijie Qin, Xuesong Feng*, Hongzhou Shang*, Pengyun Li*, Zhibing Zheng* and Song Li, \",\"doi\":\"10.1021/acs.jmedchem.5c01086\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Immunomodulatory drugs (IMiDs) are widely utilized therapies in multiple hematological cancers; however, their clinical application is frequently constrained by drug resistance. Here, though screening of diverse cereblon (CRBN) binders, comprehensive structure–activity relationships (SAR) analyses and systematic degradation profiling, <b>MGD-22</b>, a potent IKZF1/2/3 degrader featuring a phthalazinone scaffold, demonstrated nanomolar-range IC<sub>50</sub> potencies across diverse multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL) cancer cells and overcame acquired resistance to pomalidomide. <b>MGD-22</b> selectively induced robust degradation of IKZF1/2/3 in a Cullin-CRBN pathway-dependent manner, with nanomolar DC<sub>50</sub> potency. Furthermore, orally administered <b>MGD-22</b> demonstrated significant tumor growth inhibition with admirable pharmacokinetic properties and displayed s marked synergistic effects with Bruton’s tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitor, respectively, in DLBCL cancer cells. Collectively, these findings establish a rationale for triple-targeted degradation of IKZF1/2/3 and position <b>MGD-22</b> as a promising therapeutic candidate with broader applicability in hematological cancer treatment.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"68 15\",\"pages\":\"16237–16259\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01086\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01086","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of Novel Potent Triple IKZF1/2/3 Degraders for the Treatment of Hematological Cancers
Immunomodulatory drugs (IMiDs) are widely utilized therapies in multiple hematological cancers; however, their clinical application is frequently constrained by drug resistance. Here, though screening of diverse cereblon (CRBN) binders, comprehensive structure–activity relationships (SAR) analyses and systematic degradation profiling, MGD-22, a potent IKZF1/2/3 degrader featuring a phthalazinone scaffold, demonstrated nanomolar-range IC50 potencies across diverse multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL) cancer cells and overcame acquired resistance to pomalidomide. MGD-22 selectively induced robust degradation of IKZF1/2/3 in a Cullin-CRBN pathway-dependent manner, with nanomolar DC50 potency. Furthermore, orally administered MGD-22 demonstrated significant tumor growth inhibition with admirable pharmacokinetic properties and displayed s marked synergistic effects with Bruton’s tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitor, respectively, in DLBCL cancer cells. Collectively, these findings establish a rationale for triple-targeted degradation of IKZF1/2/3 and position MGD-22 as a promising therapeutic candidate with broader applicability in hematological cancer treatment.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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