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.
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 <sup>13</sup>C<sub>2</sub>-glycolate 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 in the 125 mg multiple ascending dose cohort.
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 Arg106âÂÂAsp195âÂÂTyr239 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 <sup>13</sup>C<sub>2</sub>-glycolate tracer to <sup>13</sup>C<sub>2</sub>-oxalate. CHK-336 reduces urinary oxalate excretion in mouse models of both primary hyperoxaluria 1 (Agxt knockout) and 2 (Grhpr knockout).