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

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

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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