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
  • 1. Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: [email protected].
  • 2. Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: [email protected].
  • 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: [email protected].
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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