Discovery of Novel Potent Triple IKZF1/2/3 Degraders for the Treatment of Hematological Cancers

  • J Med Chem. 2025 Aug 14;68(15):16237-16259. doi: 10.1021/acs.jmedchem.5c01086.
Ting Wei  1  2  3 ,  Shiyang Sun  1  2 ,  Xiaotong Hu  1  2 ,  Pengli Wei  1  2  4 ,  Zhiya Fan  5 ,  Jian Yan  1  2 ,  Yalei Wang  1  2  3 ,  Zhenze Qi  1  2 ,  Changkai Jia  1  2 ,  Yaqiu Mao  1  2  4 ,  Tingting Yang  6 ,  Xu Cai  1  2 ,  Bingkun Li  1  2 ,  Zhiyuan Zhao  1  2 ,  Min Qiao  1  2 ,  Yaxin Zou  1  2  4 ,  Weijie Qin  5 ,  Xuesong Feng  4 ,  Hongzhou Shang  3 ,  Pengyun Li  1  2 ,  Zhibing Zheng  1  2 ,  Song Li  1  2
Affiliations
  • 1. National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 2. State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 3. College of Chemical Engineering, North China University of Science and Technology, Tangshan 063210, China.
  • 4. School of Pharmacy, China Medical University, Shenyang 110122, China.
  • 5. State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, National Center for Protein Sciences (Beijing), Beijing 102206, China.
  • 6. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
PMID: 40747902 DOI: 10.1021/acs.jmedchem.5c01086
Abstract

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.

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