CHK-336 is a small molecule

lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...

inhibitor developed by

Chinook Therapeutics Chinook may refer to: Chinook peoples The name derives from a settlement of Indigenous people in Oregon and Washington State. * Chinookan peoples, several groups of Indigenous people of the Pacific Northwest ** Chinook Indian Nation, an organiz ...

Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...

Company). CHK-336 is a first-in-class, orally available, and

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

-targeted molecule and is being investigated for the treatment of primary

hyperoxaluria Hyperoxaluria is an excessive urinary excretion of oxalate. Individuals with hyperoxaluria often have calcium oxalate kidney stones. It is sometimes called Bird's disease, after Golding Bird, who first described the condition. Presentation Caus ...

. By inhibiting the final and only committed step in hepatic

oxalate Oxalate (systematic IUPAC name: ethanedioate) is an anion with the chemical formula . This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (), and several esters such as ...

synthesis, CHK-336 could in principle treat all forms of primary hyperoxaluria. In April 2022, a phase 1 clinical trial of CHK-336 was initiated. This trial was designed to evaluate the safety, tolerability, and pharmacokinetic profile of CHK-336 in healthy volunteers. CHK-336 was found to be generally well-tolerated in single doses up to 500 mg and multiple doses up to 60 mg for 14 days. Pharmacokinetic evaluation supported once-daily dosing, and use of a ¹³C₂-

glycolate Glycolic acid (or hydroxyacetic acid; chemical formula ) is a colorless, odorless and hygroscopic crystalline solid, highly soluble in water. It is used in various skin-care products. Glycolic acid is widespread in nature. A glycolate (sometimes s ...

tracer established proof-of-mechanism that CHK-336 blocks hepatic oxalate production. This clinical trial was paused in April 2023 upon one serious adverse event of

anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

in the 125 mg multiple ascending dose cohort.

Mechanism of action

To facilitate hepatic uptake via organic anion transporting polypeptides (OATPs), a thiazole carboxylic acid CHK-569 was chosen as the starting point in the development of CHK-336. Compounds in this series display slow-off kinetics with respect to lactate dehydrogenase A (LDHA) binding. Crystallography studies revealed that compounds in this series induce a strong interaction network between residues Arg106−Asp195−Tyr239 that drives this slow-off phenotype. In LDHA-knockout mice, CHK-336 concentrations are 10-fold lower 24 h after dosing, suggesting that target-mediated drug deposition (TMDD) mediates the long liver half-life of CHK-336. ''In vivo'' efficacy of CHK-336 was evaluated by assessing conversion of a ¹³C₂-glycolate tracer to ¹³C₂-oxalate. CHK-336 reduces urinary oxalate excretion in mouse models of both primary hyperoxaluria 1 (''

Agxt Serine—pyruvate aminotransferase is an enzyme that in humans is encoded by the ''AGXT'' gene. This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxifi ...

'' knockout) and 2 (''

Grhpr Glyoxylate reductase/hydroxypyruvate reductase is an enzyme that in humans is encoded by the ''GRHPR'' gene. This gene encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D- glycerate dehydrogenase enzymatic activities. ...

'' knockout).

References

{{reflist Thiazoles Pyrazoles Sulfonamides 4-Fluorophenyl compounds Cyclopropyl compounds Carboxylic acids