2. Academic Validation
  3. Discovery of Highly Potent and Selective IKZF2 Degraders for Cancer Immunotherapy

Discovery of Highly Potent and Selective IKZF2 Degraders for Cancer Immunotherapy

  • J Med Chem. 2026 Apr 23;69(8):9615-9634. doi: 10.1021/acs.jmedchem.6c00500.
Yalei Wang 1 2,  Zhenze Qi 2 3,  Shiyang Sun 2 3,  Ting Wei 1 2,  Pengli Wei 2 3,  Changkai Jia 2 3,  Xu Cai 2 3,  Zhiyuan Zhao 2 3,  Min Qiao 2 3,  Yaxin Zou 2 3,  Zhihui Mu 2 3,  Xiaofang Lei 2 3,  Ziyun Zhang 2 3,  Xinna Wei 2 3,  Jiatao Qi 2 3,  Sihan Cui 2 3,  Tingting Yang 4,  Xiaomei Zhuang 3,  Junhai Xiao 2 3,  Zhibing Zheng 2 3,  Hongzhou Shang 1,  Pengyun Li 2 3,  Song Li 2 3
Affiliations

Affiliations

  • 1 College of Chemical Engineering, North China University of Science and Technology, Tangshan 063210, China.
  • 2 National Engineering Research Center for the Emergency Drug, Beijing 100039, P. R. China.
  • 3 State Key Laboratory of National Security Specially Needed Medicines, Beijing100039, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 41944524 DOI: 10.1021/acs.jmedchem.6c00500
Abstract

Immunosuppressive Tregs, regulated by IKZF2, facilitate tumor immune evasion and resistance to immune checkpoint therapies. Targeted IKZF2 degradation represents a promising strategy for the development of innovative Cancer immunotherapeutics. Herein, we designed and synthesized a novel series of phthalazinone-based glutarimide derivatives, identifying compound 25 as a potent, highly selective, and rapid-acting IKZF2 molecular glue degrader. Compound 25 induced robust IKZF2 degradation (DC50 = 1.78 nM and Dmax = 93.2%) via a Cullin-CRBN-dependent pathway, while sparing Other CRBN neosubstrates and outperforming the benchmark degrader DKY709. Mechanistically, 25-induced IKZF2 deletion enhanced the proinflammatory IL-2 production and attenuated the immunosuppressive function of Tregs. Oral administration of 25 triggered rapid, profound, and sustained IKZF2 degradation in mice spleen and thymus. As monotherapy, 25 significantly suppressed B16F tumor growth, and 25 combined with anti-PD-1 antibody therapy exhibited marked synergistic effects. Together, our findings demonstrate 25 as a promising IKZF2 Degrader for advancing Cancer Immunotherapy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z