Lipid transfer/lipopolysaccharide binding proteins

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Lipid transfer/lipopolysaccharide binding proteins

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The lipid transfer/lipopolysaccharide binding protein (LT/LBP) family are structurally related proteins that are able to bind phospholipids and lipopolysaccharides. Family members share significant amino acid similarity and exon/intron organisation. Cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are plasma proteins that are necessary for the catabolism of high-density lipoproteins (HDL), and they have been associated with the pathogenesis of atherosclerosis. CETP has been extensively investigated as a drug target for the development of agents to treat/prevent atherosclerotic cardiovascular disease and other diseases associated with lipoprotein metabolism. Other members of this protein family include lipopolysaccharide binding protein (LBP; a plasma protein) and bactericidal/permeability-increasing protein (BPI; detected in neutrophil and eosinophil granules) which both bind to bacterial endotoxins and modulate the host response to infections by Gram-negative bacteria.

Targets

3248

cholesteryl ester transfer protein Show summary »« Hide summary

Target Id

3248

Nomenclature

cholesteryl ester transfer protein

Previous and unofficial names

BPIFF | BPI fold containing family F

Genes

CETP (Hs)

Ensembl ID

ENSG00000087237 (Hs)

UniProtKB AC

P11597 (Hs)

Inhibitors

anacetrapib pIC₅₀ 7.8 [7]

evacetrapib pIC₅₀ 7.6 [2]

MK-8262 pIC₅₀ 7.3 [9]

DRL-17822 pIC₅₀ >6.0 [1]

dalcetrapib pIC₅₀ 5.4 [10]

obicetrapib [4]

Comment

The CETP protein transfers cholesteryl ester and triglyceride between lipoprotein particles, and regulates reverse cholesterol transport (which facilitates the removal of excess cholesterol from peripheral tissues for elimination in the liver). Defects in CETP are a cause of hyperalphalipoproteinemia 1 (HALP1). CETP was validated as a clinical target for the development of agents to treat/prevent atherosclerotic cardiovascular disease and other dyslipidemias. Despite extensive investigation, to date (2023) no CETP inhibitor has demonstrated sufficient safety and/or efficacy in a clinical study to justify continued development [3,5-6,8].

References

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1. Baruah A, De D, Khanna I, Pillarisetti S, Maitra S, Alexander C, Sreenu J, Dager I. (2007) Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors. Patent number: US20070015758A1. Assignee: Reddy US Therapeutics Inc. Priority date: 31/12/2004. Publication date: 18/01/2007.

2. Fernandez MC, Escribano A, Mateo AI, Parthasarathy S, Martin de la Nava EM, Wang X, Cockerham SL, Beyer TP, Schmidt RJ, Cao G et al.. (2012) Design, synthesis and structure-activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors. Bioorg Med Chem Lett, 22 (9): 3056-62. [PMID:22497761]

3. Filippatos TD, Kei A, Elisaf MS. (2017) Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias?. Diseases, 5 (4). [PMID:28961179]

4. Ford J, Lawson M, Fowler D, Maruyama N, Mito S, Tomiyasu K, Kinoshita S, Suzuki C, Kawaguchi A, Round P et al.. (2014) Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Br J Clin Pharmacol, 78 (3): 498-508. [PMID:24628035]

5. Hovingh GK, Kastelein JJ, van Deventer SJ, Round P, Ford J, Saleheen D, Rader DJ, Brewer HB, Barter PJ. (2015) Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet, 386 (9992): 452-60. [PMID:26047975]

6. Joy TR, Hegele RA. (2008) The failure of torcetrapib: what have we learned?. Br J Pharmacol, 154 (7): 1379-81. [PMID:18536741]

7. Smith CJ, Ali A, Hammond ML, Li H, Lu Z, Napolitano J, Taylor GE, Thompson CF, Anderson MS, Chen Y et al.. (2011) Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: modifications of the oxazolidinone ring leading to the discovery of anacetrapib. J Med Chem, 54 (13): 4880-95. [PMID:21682257]

8. Tardif JC, Pfeffer MA, Kouz S, Koenig W, Maggioni AP, McMurray JJV, Mooser V, Waters DD, Grégoire JC, L'Allier PL et al.. (2022) Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial. Eur Heart J, 43 (39): 3947-3956. [PMID:35856777]

9. Vachal P, Duffy JL, Campeau LC, Amin RP, Mitra K, Murphy BA, Shao PP, Sinclair PJ, Ye F, Katipally R et al.. (2021) Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties. J Med Chem, 64 (18): 13215-13258. [PMID:34375108]

10. Yamada K, Brousseau M, Honma W, Iimura A, Imase H, Iwaki Y, Kawanami T, LaSala D, Liang G, Mitani H et al.. (2017) Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma. J Med Chem, 60 (20): 8466-8481. [PMID:29035537]

How to cite this family page

Database page citation:

Lipid transfer/lipopolysaccharide binding proteins. Accessed on 28/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1088.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Buneman OP, Faccenda E, Harding SD, Spedding M, Cidlowski JA, Fabbro D, Davenport AP, Striessnig J, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. Br J Pharmacol. 180 Suppl 2:S1-22.