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

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.

 

Comments:

That's a fascinating discovery! NVP-DKY709 seems like a promising avenue in cancer immunotherapy. It's remarkable how the selective degradation of IKZF2 could potentially alter the immune response by affecting Treg cells and T-effector cells, ultimately impacting tumor growth.

This molecular approach appears to have shown effectiveness in preclinical models by targeting IKZF2 without affecting IKZF1/3, suggesting a potential avenue for therapeutic intervention without disturbing other crucial immune functions.

The ability of NVP-DKY709 to enhance immunization responses in non-human primates and delay tumor growth in mice with humanized immune systems suggests its potential as an immune-modulating agent in cancer treatment. It'll be intriguing to see how this progresses in clinical investigations and its implications for cancer immunotherapy.

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E1204 NVP-DKY709 NVP-DKY709 is a potent IKZF2 inhibitor for the treatment of cancers.

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