Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Feb 2

PMID 36727857

Authors

Sven Thamm

Marina K Willwacher

Gary E Aspnes

Tom Bretschneider

Nicholas F Brown

Silke Buschbom-Helmke

Thomas Fox

Emanuele M Gargano

Daniel Grabowski

Christoph Hoenke

Damian Matera

Katja Mueck

Stefan Peters

Sophia Reindl

Doris Riether

Matthias Schmid

Christofer S Tautermann

Aaron M Teitelbaum

Cornelius Trunkle

Thomas Veser

Martin Winter

Lars Wortmann

Affiliations

Soon will be listed here.

Abstract

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor . Through high-throughput screening (HTS), using estradiol as substrate, compound was identified and selected for subsequent optimization resulting in compound . In addition to the characterization of compound for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD dependency was investigated. To support Open Science, the chemical HSD17B13 probe will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.

Citing Articles

Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants.

Garnsey M, Wang Y, Edmonds D, Sammons M, Reidich B, Ahn Y Nat Commun. 2025; 16(1):297.

PMID: 39746932 PMC: 11697577. DOI: 10.1038/s41467-024-54487-5.

Identifying potential therapeutic targets in lung adenocarcinoma: a multi-omics approach integrating bulk and single-cell RNA sequencing with Mendelian randomization.

Chen Y, Li E, Chang Z, Zhang T, Song Z, Wu H Front Pharmacol. 2024; 15:1433147.

PMID: 39092217 PMC: 11291359. DOI: 10.3389/fphar.2024.1433147.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

Nakamura K, Kambayashi A, Onoue S Pharm Res. 2024; 41(4):673-685.

PMID: 38472609 PMC: 11636765. DOI: 10.1007/s11095-024-03669-3.

Drug development advances in human genetics-based targets.

Zhang X, Yu W, Li Y, Wang A, Cao H, Fu Y MedComm (2020). 2024; 5(2):e481.

PMID: 38344397 PMC: 10857782. DOI: 10.1002/mco2.481.

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis.

Wang Y, Yu H, Cen Z, Zhu Y, Wu W Metabol Open. 2024; 21:100267.

PMID: 38187470 PMC: 10770762. DOI: 10.1016/j.metop.2023.100267.

References

Paternostro R, Staufer K, Traussnigg S, Stattermayer A, Halilbasic E, Keritam O . Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease. Hepatol Int. 2021; 15(4):922-933. PMC: 8382644. DOI: 10.1007/s12072-021-10200-y. View

Foroozesh M, Primrose G, Guo Z, Bell L, Alworth W, Guengerich F . Aryl acetylenes as mechanism-based inhibitors of cytochrome P450-dependent monooxygenase enzymes. Chem Res Toxicol. 1997; 10(1):91-102. DOI: 10.1021/tx960064g. View

Ma Y, Brown P, Lin D, Ma J, Feng D, Belyaeva O . 17-Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury. Hepatology. 2020; 73(5):1701-1716. PMC: 8627256. DOI: 10.1002/hep.31517. View

Rufer A . Drug discovery for enzymes. Drug Discov Today. 2021; 26(4):875-886. DOI: 10.1016/j.drudis.2021.01.006. View

Schuster D, Nashev L, Kirchmair J, Laggner C, Wolber G, Langer T . Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries. J Med Chem. 2008; 51(14):4188-99. DOI: 10.1021/jm800054h. View

Senisterra G, Chau I, Vedadi M . Thermal denaturation assays in chemical biology. Assay Drug Dev Technol. 2011; 10(2):128-36. DOI: 10.1089/adt.2011.0390. View

Gellert-Kristensen H, Nordestgaard B, Tybjaerg-Hansen A, Stender S . High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase-Lowering Effect of a HSD17B13 Variant. Hepatology. 2019; 71(1):56-66. DOI: 10.1002/hep.30799. View

Lee C, Jordan D, Stoller J, Kibblewhite R, Wagschal K . Biochemical characterization of Caulobacter crescentus xylose dehydrogenase. Int J Biol Macromol. 2018; 118(Pt A):1362-1367. DOI: 10.1016/j.ijbiomac.2018.06.124. View

Gollner A, Koster M, Nicklin P, Trieselmann T, Klein E, Vlach J . opnMe.com: a digital initiative for sharing tools with the biomedical research community. Nat Rev Drug Discov. 2022; 21(7):475-476. DOI: 10.1038/d41573-022-00071-9. View

10.

Tu M, Mathiowetz A, Pfefferkorn J, Cameron K, Dow R, Litchfield J . Medicinal chemistry design principles for liver targeting through OATP transporters. Curr Top Med Chem. 2013; 13(7):857-66. DOI: 10.2174/1568026611313070008. View

11.

Luukkonen P, Tukiainen T, Juuti A, Sammalkorpi H, Haridas P, Niemela O . Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight. 2020; 5(5). PMC: 7141400. DOI: 10.1172/jci.insight.132158. View

12.

Chen H, Zhang Y, Guo T, Yang F, Mao Y, Li L . Genetic variant rs72613567 of HSD17B13 gene reduces alcohol-related liver disease risk in Chinese Han population. Liver Int. 2020; 40(9):2194-2202. PMC: 7496237. DOI: 10.1111/liv.14616. View

13.

Winter M, Bretschneider T, Kleiner C, Ries R, Hehn J, Redemann N . Establishing MALDI-TOF as Versatile Drug Discovery Readout to Dissect the PTP1B Enzymatic Reaction. SLAS Discov. 2018; 23(6):561-573. DOI: 10.1177/2472555218759267. View

14.

Beaudry F, Ross A, Lema P, Vachon P . Pharmacokinetics of vanillin and its effects on mechanical hypersensitivity in a rat model of neuropathic pain. Phytother Res. 2009; 24(4):525-30. DOI: 10.1002/ptr.2975. View

15.

Carter A, Kraemer O, Zwick M, Mueller-Fahrnow A, Arrowsmith C, Edwards A . Target 2035: probing the human proteome. Drug Discov Today. 2019; 24(11):2111-2115. DOI: 10.1016/j.drudis.2019.06.020. View

16.

Liao T, Oehme F . Tissue distribution and plasma protein binding of [14C]phenol in rats. Toxicol Appl Pharmacol. 1981; 57(2):220-5. DOI: 10.1016/0041-008x(81)90282-9. View

17.

Muller S, Ackloo S, Al Chawaf A, Al-Lazikani B, Antolin A, Baell J . Target 2035 - update on the quest for a probe for every protein. RSC Med Chem. 2022; 13(1):13-21. PMC: 8792830. DOI: 10.1039/d1md00228g. View

18.

Ortiz de Montellano P, Kunze K . Self-catalyzed inactivation of hepatic cytochrome P-450 by ethynyl substrates. J Biol Chem. 1980; 255(12):5578-85. View

19.

Li Z, Bao X, Bai X, Zhang G, Wang J, Zhu M . Design, Synthesis, and Biological Evaluation of Phenol Bioisosteric Analogues of 3-Hydroxymorphinan. Sci Rep. 2019; 9(1):2247. PMC: 6381151. DOI: 10.1038/s41598-019-38911-1. View

20.

Ting Y, Kong A, Zain S, Chan W, Tan H, Mohamed Z . Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort. Clin Mol Hepatol. 2021; 27(3):486-498. PMC: 8273635. DOI: 10.3350/cmh.2020.0162. View