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Article ; Online: Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.

Bonazzi, Simone / d'Hennezel, Eva / Beckwith, Rohan E J / Xu, Lei / Fazal, Aleem / Magracheva, Anna / Ramesh, Radha / Cernijenko, Artiom / Antonakos, Brandon / Bhang, Hyo-Eun C / Caro, Roxana García / Cobb, Jennifer S / Ornelas, Elizabeth / Ma, Xiaolei / Wartchow, Charles A / Clifton, Matthew C / Forseth, Ry R / Fortnam, Bethany Hughes / Lu, Hongbo /
Csibi, Alfredo / Tullai, Jennifer / Carbonneau, Seth / Thomsen, Noel M / Larrow, Jay / Chie-Leon, Barbara / Hainzl, Dominik / Gu, Yi / Lu, Darlene / Meyer, Matthew J / Alexander, Dylan / Kinyamu-Akunda, Jacqueline / Sabatos-Peyton, Catherine A / Dales, Natalie A / Zécri, Frédéric J / Jain, Rishi K / Shulok, Janine / Wang, Y Karen / Briner, Karin / Porter, Jeffery A / Tallarico, John A / Engelman, Jeffrey A / Dranoff, Glenn / Bradner, James E / Visser, Michael / Solomon, Jonathan M

Cell chemical biology

2023  Volume 30, Issue 3, Page(s) 235–247.e12

Abstract: Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 ... ...

Abstract Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.
MeSH term(s) Animals ; Humans ; Mice ; Ikaros Transcription Factor ; Immunotherapy ; Neoplasms/therapy ; Neoplasms/metabolism ; T-Lymphocytes, Regulatory/metabolism ; Transcription Factors/metabolism
Chemical Substances Ikaros Transcription Factor (148971-36-2) ; IKZF2 protein, human ; Transcription Factors ; Ikzf2 protein, mouse
Language English
Publishing date 2023-03-01
Publishing country United States
Document type Journal Article ; Research Support, Non-U.S. Gov't
ISSN 2451-9448
ISSN (online) 2451-9448
DOI 10.1016/j.chembiol.2023.02.005
Database MEDical Literature Analysis and Retrieval System OnLINE

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