CHK-336
Chemical compound
From Wikipedia, the free encyclopedia
CHK-336 is a small molecule lactate dehydrogenase inhibitor developed by Chinook Therapeutics (a Novartis Company). CHK-336 is a first-in-class, orally available, and liver-targeted molecule and is being investigated for the treatment of primary hyperoxaluria. By inhibiting the final and only committed step in hepatic oxalate synthesis, CHK-336 could in principle treat all forms of primary hyperoxaluria.[1]
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| IUPAC name
2-[5-(cyclopropylmethyl)-3-(4-fluorophenyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid | |
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| Properties | |
| C24H20F2N4O4S2 | |
| Molar mass | 530.56 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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In April 2022, a phase 1 clinical trial of CHK-336 was initiated.[2] 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.[3][4] Pharmacokinetic evaluation supported once-daily dosing, and use of a 13C2-glycolate tracer established proof-of-mechanism that CHK-336 blocks hepatic oxalate production.[3][4] This clinical trial was paused in April 2023 upon one serious adverse event of anaphylaxis in the 125 mg multiple ascending dose cohort.[5]
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.[6][7] Compounds in this series display slow-off kinetics with respect to lactate dehydrogenase A (LDHA) binding.[7] Crystallography studies revealed that compounds in this series induce a strong interaction network between residues Arg106−Asp195−Tyr239 that drives this slow-off phenotype.[7] 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.[7]
In vivo efficacy of CHK-336 was evaluated by assessing conversion of a 13C2-glycolate tracer to 13C2-oxalate.[7][8] CHK-336 reduces urinary oxalate excretion in mouse models of both primary hyperoxaluria 1 (Agxt knockout) and 2 (Grhpr knockout).[7]