STF-62247 blocks late stages of autophagy by disrupting lysosomal physiology
Bibliographic record
Abstract
ABSTRACT STF-62247 was previously identified as a promising compound able to selectively target the loss of the tumor suppressor gene von Hippel-Lindau (VHL) in renal cell carcinomas. This present work investigates the effect of STF-62247 on the autophagic flux. Our investigations show that STF-62247 blocks late stages of autophagy through lysosomal disruption. Indeed, STF-62247 localizes at lysosomes and causes unregulated swelling of these acidic compartments in VHL-mutated cells, linking a potential role for VHL in lysosomal integrity. Knock-outs of BECN1 and ATG5 were able to rescue the viability of VHL-mutated cells in response to STF-62247 but did not rescue the lysosomal swelling. In fact, neutralizing the lysosomal pH by inhibiting the vacuolar H+-ATPase completely rescued this phenotype. Moreover, we show that STF-62247 disrupts endocytic routes and causes cathepsin D trafficking defects. This mechanistic study is the first to characterize STF-62447 as a novel lysosomotropic compound. Importantly, our study re-classifies STF-62247 as a blocker of later stages of autophagy and highlights its potential usage as a powerful new tool for endocytic and autophagy-related research.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".