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

Journal Article · · Cell Chemical Biology
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  1. Novartis Institutes for Biomedical Research, Cambridge, MA (United States)
  2. Novartis Institutes for Biomedical Research, Emeryville, CA (United States)
  3. Novartis Institutes for Biomedical Research, East Hanover, NJ (United States)
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
2422672
Journal Information:
Cell Chemical Biology, Journal Name: Cell Chemical Biology Journal Issue: 3 Vol. 30; ISSN 2451-9456
Publisher:
Cell PressCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
IKZF2
cereblon
drug discovery
glue degrader
regulatory T cells
targeted protein degradation