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. Epub 2023 Mar 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Ikaros Transcription Factor
  • Immunotherapy
  • Mice
  • Neoplasms* / metabolism
  • Neoplasms* / therapy
  • T-Lymphocytes, Regulatory / metabolism
  • Transcription Factors* / metabolism

Substances

  • Ikaros Transcription Factor
  • IKZF2 protein, human
  • Transcription Factors
  • Ikzf2 protein, mouse