2. Academic Validation
  3. Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

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

  • Cell Chem Biol. 2023 Mar 16;30(3):235-247.e12. doi: 10.1016/j.chembiol.2023.02.005.
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

Affiliations

  • 1 Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: simone.bonazzi@novartis.com.
  • 2 Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: eva.dhennezel@novartis.com.
  • 3 Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 4 Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
  • 5 Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
  • 6 Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: jonathan.solomon@novartis.com.
PMID: 36863346 DOI: 10.1016/j.chembiol.2023.02.005
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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