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. 2023 Mar 16;30(3):235-247.e12.
doi: 10.1016/j.chembiol.2023.02.005. Epub 2023 Mar 1.

Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

Simone Bonazzi  1 , Eva d'Hennezel  2 , Rohan E J Beckwith  3 , Lei Xu  3 , Aleem Fazal  3 , Anna Magracheva  3 , Radha Ramesh  3 , Artiom Cernijenko  3 , Brandon Antonakos  3 , Hyo-Eun C Bhang  3 , Roxana García Caro  3 , Jennifer S Cobb  3 , Elizabeth Ornelas  4 , Xiaolei Ma  4 , Charles A Wartchow  4 , Matthew C Clifton  4 , Ry R Forseth  5 , Bethany Hughes Fortnam  3 , Hongbo Lu  3 , Alfredo Csibi  3 , Jennifer Tullai  3 , Seth Carbonneau  3 , Noel M Thomsen  3 , Jay Larrow  3 , Barbara Chie-Leon  4 , Dominik Hainzl  3 , Yi Gu  3 , Darlene Lu  3 , Matthew J Meyer  3 , Dylan Alexander  3 , Jacqueline Kinyamu-Akunda  5 , Catherine A Sabatos-Peyton  3 , Natalie A Dales  3 , Frédéric J Zécri  3 , Rishi K Jain  3 , Janine Shulok  3 , Y Karen Wang  3 , Karin Briner  3 , Jeffery A Porter  3 , John A Tallarico  3 , Jeffrey A Engelman  3 , Glenn Dranoff  3 , James E Bradner  3 , Michael Visser  3 , Jonathan M Solomon  6
Affiliations
Free article

Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

Simone Bonazzi et al. Cell Chem Biol. .
Free article

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.

Keywords: IKZF2; cereblon; drug discovery; glue degrader; regulatory T cells; targeted protein degradation.

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Conflict of interest statement

Declaration of interests All authors are past or current employees of Novartis Institutes for Biomedical Research. Some of the authors have patents related to this work: WO2019038717, 3-(1-oxoisoindolin-2-YL)Piperidine-2-6-Dione derivatives and uses thereof (R.E.J.B., S.B., A.C., A.F., and M.V.); and WO2020128972, Dosing regimen and pharmaceutical combinations comprising 3-(1-oxoisoindolin-2-YL)Piperidine-2-6-Dione derivatives (S.B., E.d’H., G.D., R.R.F., D.H., and J.K.-A.).

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