Chemistry:CHK-336
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]
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]
References
- ↑ Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alex; Chefson, Amandine; Chong, Oliver; Ding, Jim; Dumais, Valerie; Gaudreault, Samuel et al. (October 2020). "Discovery of CHK-336: A First-in-Class, Liver-Targeted, Small Molecule Inhibitor of Lactate Dehydrogenase for the Treatment of Primary Hyperoxaluria: PO1620" (in en). Journal of the American Society of Nephrology 31 (10S): 514. doi:10.1681/ASN.20203110S1514a. ISSN 1046-6673. https://journals.lww.com/10.1681/ASN.20203110S1514a.
- ↑ Clinical trial number NCT05367661 at ClinicalTrials.gov
- ↑ 3.0 3.1 Tong, Vincent; Schwartz, Brian; Lam, Chun; Knight, John; Fargue, Sonia; Wagner, David A; Wong, Harvey; Wang, Lei et al. (2023-06-14). "#4328 CHK-336, A First-In-Class Orally Administered LDH Inhibitor: Safety, Pk and Target Engagement in a First-In-Human Phase 1 Healthy Volunteer Study" (in en). Nephrology Dialysis Transplantation 38 (Supplement_1). doi:10.1093/ndt/gfad063a_4328. ISSN 0931-0509. https://academic.oup.com/ndt/article/doi/10.1093/ndt/gfad063a_4328/7195646.
- ↑ 4.0 4.1 "Chinook Therapeutics Presents Data from CHK-336 Phase 1 Trial in Healthy Volunteers and New Insights into the Role of Failed Repair in Chronic Kidney Disease at the 60th European Renal Association (ERA) Congress". GlobeNewswire News Room (Press release). Chinook Therapeutics. 2023-06-17. Retrieved 2025-04-17.
- ↑ "Chinook Therapeutics Announces Voluntary Pause in Dosing of CHK-336 in Ongoing Phase 1 Clinical Trial in Healthy Volunteers". GlobeNewswire News Room (Press release). Chinook Therapeutics. 2023-04-11. Retrieved 2025-04-17.
- ↑ Oballa, Renata M.; Belair, Liette; Black, W. Cameron; Bleasby, Kelly; Chan, Chi Chung; Desroches, Carole; Du, Xiaobing; Gordon, Robert et al. (2011-07-28). "Development of a Liver-Targeted Stearoyl-CoA Desaturase (SCD) Inhibitor (MK-8245) to Establish a Therapeutic Window for the Treatment of Diabetes and Dyslipidemia" (in en). Journal of Medicinal Chemistry 54 (14): 5082–5096. doi:10.1021/jm200319u. ISSN 0022-2623. PMID 21661758. https://pubs.acs.org/doi/10.1021/jm200319u.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alexandre; Sheng, Tao; Wu, Joyce; Ding, Jinyue; Gaudreault, Samuel; Chong, Oliver et al. (2025-04-07). "Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment" (in en). Journal of the American Society of Nephrology. doi:10.1681/ASN.0000000690. ISSN 1046-6673. PMID 40193200. https://journals.lww.com/10.1681/ASN.0000000690.
- ↑ Garrelfs, Sander F.; van Harskamp, Dewi; Peters-Sengers, Hessel; van den Akker, Chris H. P.; Wanders, Ronald J. A.; Wijburg, Frits A.; van Goudoever, Johannes B.; Groothoff, Jaap W. et al. (2021-12-01). "Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients". Journal of the American Society of Nephrology 32 (12): 3175–3186. doi:10.1681/ASN.2021060729. ISSN 1533-3450. PMID 34686543.
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