8DEY

Ternary complex structure of Cereblon-DDB1 bound to IKZF2(ZF2,3) and the molecular glue DKY709

Summary for 8DEY

• Entry DOI: 10.2210/pdb8dey/pdb
• Descriptor: Protein cereblon, DNA damage-binding protein 1, Zinc finger protein Helios, ... (5 entities in total)
• Functional Keywords: e3 ligase, molecular glue, complex, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 286534.37

Authors

Ma, X.,Ornelas, E.,Clifton, M.C. (deposition date: 2022-06-21, release date: 2023-03-08, Last modification date: 2024-10-30)

Primary citation

Bonazzi, S.,d'Hennezel, E.,Beckwith, R.E.J.,Xu, L.,Fazal, A.,Magracheva, A.,Ramesh, R.,Cernijenko, A.,Antonakos, B.,Bhang, H.C.,Caro, R.G.,Cobb, J.S.,Ornelas, E.,Ma, X.,Wartchow, C.A.,Clifton, M.C.,Forseth, R.R.,Fortnam, B.H.,Lu, H.,Csibi, A.,Tullai, J.,Carbonneau, S.,Thomsen, N.M.,Larrow, J.,Chie-Leon, B.,Hainzl, D.,Gu, Y.,Lu, D.,Meyer, M.J.,Alexander, D.,Kinyamu-Akunda, J.,Sabatos-Peyton, C.A.,Dales, N.A.,Zecri, F.J.,Jain, R.K.,Shulok, J.,Wang, Y.K.,Briner, K.,Porter, J.A.,Tallarico, J.A.,Engelman, J.A.,Dranoff, G.,Bradner, J.E.,Visser, M.,Solomon, J.M.
Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.
Cell Chem Biol, 30:235-247.e12, 2023

PubMed 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.

PubMed: 36863346
DOI: 10.1016/j.chembiol.2023.02.005

Experimental method

X-RAY DIFFRACTION (3.7 Å)