Selective Small-Molecule Activator of Patient-Derived GPX4 Variant
Bibliographic record
Abstract
Glutathione peroxidase 4 (GPX4) is distinguished from other members of the GPX family as being the enzyme capable of reducing phospholipid hydroperoxides within cellular membranes and therefore protecting cells from ferroptosis, a form of iron-driven cell death involving lipid peroxidation. We previously identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation and a substantial loss of GPX4 enzymatic activity, in patients with Sedaghatian-type spondylometaphyseal dysplasia (SSMD), an ultrarare progressive disorder. To explore whether selective binding and correction of the loss of enzyme activity observed with this variant is possible, we screened 2.8 billion compounds in a DNA-encoded chemical library and identified compounds with remarkably selective binding affinities with the R152H variant (GPX4 R152H ) over wild-type (GPX4 WT ). Our structural optimization of these compounds led to the identification of analogues with improved potency for R152H GPX4. The most promising compounds selectively restored the enzyme activity of GPX4 R152H and specifically increased the viability of fibroblast and lymphoblast cells developed from an SSMD patient with the homozygous R152H variation but not control cells from a healthy parent or HEK293T cells undergoing ferroptosis induced by a wild-type GPX4 inhibitor. This approach represents a low-cost, high-throughput, and generalizable approach to identify targeted small-molecule therapeutics for missense variants, which features the potential to be broadly applied to diseases that bear point mutations on crucial proteins, including cancers.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".