CHK-336

Last updated
CHK-336
CHK-336.png
Names
IUPAC name
2-[5-(cyclopropylmethyl)-3-(4-fluorophenyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C24H20F2N4O4S2/c25-16-6-4-15(5-7-16)22-17(9-14-3-8-21(18(26)10-14)36(27,33)34)20(11-13-1-2-13)30(29-22)24-28-19(12-35-24)23(31)32/h3-8,10,12-13H,1-2,9,11H2,(H,31,32)(H2,27,33,34)
    Key: XAHAUTPHLZAEKK-UHFFFAOYSA-N
  • NS(=O)(=O)C1=C(F)C=C(CC2=C(CC3CC3)N(N=C2C4=CC=C(F)C=C4)C5=NC(=CS5)C(O)=O)C=C1
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).

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

Human Lactate Dehydrogenase A in Complex with Inhibitor CHK-336 (PDB: 8FW6). CHK-336 shown in green. NADH co-factor shown in bottom left. Residues Arg106, Asp195, Tyr239 labeled. CHK-336 correct label 8FW6.png
Human Lactate Dehydrogenase A in Complex with Inhibitor CHK-336 (PDB: 8FW6). CHK-336 shown in green. NADH co-factor shown in bottom left. Residues Arg106, Asp195, Tyr239 labeled.

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

  1. ↑ Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alex; Chefson, Amandine; Chong, Oliver; Ding, Jim; Dumais, Valerie; Gaudreault, Samuel; Gomez, Robert; Guthrie, James; Holmes, Ross P.; King, Andrew J.; Knight, John; Lester, Jeff; Lowther, W. T. (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" . Journal of the American Society of Nephrology. 31 (10S): 514. doi:10.1681/ASN.20203110S1514a. ISSN   1046-6673.
  2. ↑ Clinical trial number NCT05367661 at ClinicalTrials.gov
  3. 1 2 Tong, Vincent; Schwartz, Brian; Lam, Chun; Knight, John; Fargue, Sonia; Wagner, David A; Wong, Harvey; Wang, Lei; Kocinsky, Hetal; Fauvelle, Valerie; King, Andrew (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". Nephrology Dialysis Transplantation. 38 (Supplement_1). doi:10.1093/ndt/gfad063a_4328. ISSN   0931-0509.
  4. 1 2 "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.
  5. ↑ "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.
  6. ↑ Oballa, Renata M.; Belair, Liette; Black, W. Cameron; Bleasby, Kelly; Chan, Chi Chung; Desroches, Carole; Du, Xiaobing; Gordon, Robert; Guay, Jocelyne; Guiral, Sebastien; Hafey, Michael J.; Hamelin, Emelie; Huang, Zheng; Kennedy, Brian; Lachance, Nicolas (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" . Journal of Medicinal Chemistry. 54 (14): 5082–5096. doi:10.1021/jm200319u. ISSN   0022-2623. PMID   21661758.
  7. 1 2 3 4 5 6 Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alexandre; Sheng, Tao; Wu, Joyce; Ding, Jinyue; Gaudreault, Samuel; Chong, Oliver; Surendradoss, Jayakumar; Gomez, Robert; Lester, Jeffrey; Dumais, Valerie; Li, Xingsheng; Gumpena, Rajesh; Hall, Matthew D. (2025-04-07). "Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment" . Journal of the American Society of Nephrology. doi:10.1681/ASN.0000000690. ISSN   1046-6673. PMID   40193200.
  8. ↑ 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.; Schierbeek, Henk; Oosterveld, Michiel J. S. (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. PMC   8638398 . PMID   34686543.
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