Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small-Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment
Bibliographic record
Abstract
Key Points Primary hyperoxalurias are genetic diseases defined by elevated hepatic oxalate production and higher incidence of kidney stones. Lactate dehydrogenase A catalyzes the final and committed step in hepatic oxalate synthesis and represents a potential therapeutic target for primary hyperoxalurias. CHK-336 is a liver-targeted, small-molecule lactate dehydrogenase A inhibitor with potential to treat diseases associated with elevated oxalate production. Background Primary hyperoxalurias (PH) 1–3 are genetic diseases defined by elevated hepatic oxalate production and higher incidence of calcium oxalate kidney stones and potentially kidney failure. There are two approved agents available for PH1, and there are no approved therapies for PH2 or PH3. Lactate dehydrogenase A catalyzes the final step in hepatic oxalate synthesis and represents a potential therapeutic target for PH and other forms of hyperoxaluria associated with increased oxalate production. Methods Potent and selective lactate dehydrogenase (LDH) inhibitors with liver-targeted tissue distribution were identified and characterized in enzymatic, cellular, and in vivo models. Results We identified CHK-336, a novel oral small-molecule that demonstrates potent and selective inhibition of the human LDH enzyme and its activity in hepatocyte assays across multiple species, including hepatocytes isolated from PH1 mice. CHK-336 demonstrated a favorable liver distribution profile in mice, rats, and monkeys that was dependent on hepatic uptake by organic anion-transporting polypeptide transporters and target-mediated drug binding. In a rat pharmacodynamic model, CHK-336 inhibited conversion of 13 C 2 -glycolate to 13 C 2 -oxalate in a dose-dependent manner. In a PH1 mouse model, once-daily oral dosing of CHK-336 produced robust and dose-dependent reductions in urinary oxalate to the normal range. Seven days of treatment with CHK-336 also resulted in a significant reduction in urinary oxalate in a PH2 mouse model. Conclusions In conclusion, CHK-336 is a potent, liver-targeted, small-molecule LDH inhibitor that suppressed urinary oxalate production in a rat pharmacodynamic model and mouse models of PH1 and PH2.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.003 | 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".