Helios

April 2022

Helios

The transcription factor Helios (IKZF2), a member of the Ikaros transcription factor family, is expressed in 60–70% of T regulatory (Treg) cells. It is a known regulator of immune response due to its role inmaintaining the suppressive activity of Treg. In the absence of Helios, the immunological self-tolerance from Treg is disrupted, its concentration increases and causes a series of reactions that result in a strong immune system response (to foreign and self-tissues). 

Such unwanted reactions during infection could instead be advantageous in fighting cancer. Namely, the abundant Treg cells and enhanced immune system are more active against cancer cells (that by nature have the ability to “escape” the immune system by “masking” themselves as normal cells). 

Therefore, Helios becomes an attractive immune-oncology target. But so far, it has been hard to drug and thus there are no existing therapies that can modulate its activity.

Recently, work has been conducted in Boston exploiting a molecular glue approach. It redirects an E3 ubiquitin ligase to the transcription factor Helios. They used already known imide compounds on other Ikaros family proteins -i.e. Ikaros and Aiolos- to develop a specific molecular glue for Helios.

Thanks to sequence comparison, they identified a particular difference in the second zinc finger portion of the protein compared to Ikaros/Aiolos: glutamine is replaced by histidine. 

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Left side: Comparison of Ikaros and Helios protein sequences, pocket view. Right side: Binding site of Cereblon/Ikaros (PDB structure 6H0F), with a highlight on Gln146 in the 3D viewer. ligand-protein interactions are shown by dashed lines. The comparison was done with 3decision - a protein structure repository that allows you to easily perform 2D and 3D pocket comparisons.

This substitution can be easily detected in the 3decision knowledge management platform using the Sequence Explorer mode. Just load Ikaros PDB structure 6H0F (2018), then add Helios sequence (Uniprto identifier IKZF2_HUMAN) and you will be able to spot binding site differences.

They also observed different facts for Ikaros mutants compared to the wild-type: Q146H led to reduced imide-induced CRBN binding and Q146A showed a similar CRBN binding. It allows to understand that it is a histidine steric/electronic hindrance and not a loss of interactions with glutamine that is responsible for the decrease in CRBN binding affinity. 

Thanks to these structural insights, scientists were able to go through the ideation process and propose a synthesis strategy for more flexible compounds by modifying the CRBN-binding core. After several optimization steps, they managed to obtain potent degraders (ALV1 and ALV2). ALV1 was also cocrystallized with Cereblon/Helios complex (PDB structure 7LPS ).