TARGETING HUMAN FATTY ACID SYNTHASE IN CANCER THERAPY: STRUCTURAL INSIGHTS AND SAR OF DOMAIN SPECIFIC INHIBITOR
DOI:
https://doi.org/10.22159/ijap.2026v18i3.57640Keywords:
Human fatty acid synthase, Malonyl acyl transacylase, Ketoacyl synthase, Dehydratase, Ketoacyl reductase, Thioesterase, Enoyl reductaseAbstract
Fatty acid synthase is a key enzyme in humans that drives the biosynthesis of lipids essential for energy storage and cell membrane formation. Upregulation of FAS is significantly seen in cancer cells due to increased demands of lipids and cell proliferation. Cancer cells rely heavily on fatty acid synthesis to sustain their growth and maintain their malignant characteristics. Over the past two decades, FAS has gained considerable attention as a potential target for cancer therapy, as inhibiting this enzyme could disrupt lipid biosynthesis and impair cancer cell viability. Among the various inhibitors developed so far, TVB-2640 is the only one that has advanced into clinical trials. Here we discuss in detail about the structure and function of various domains of human fatty acid synthase enzyme with its inhibitors. In this review detailed of inhibitors for each domain are discussed. Review highlights how specific modifications to the inhibitor structure can enhance their binding affinity and selectivity towards each domain of FAS. By focusing on the Structural Activity Relationship, we aim to offer insights into the rational design of novel inhibitors that can effectively target FAS in cancer cells, thereby providing new avenues for cancer therapy.
References
1. Batchuluun B, Pinkosky SL, Steinberg GR. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat Rev Drug Discov. 2022;21(4):283-305. doi: 10.1038/s41573-021-00367-2.
2. Valli A, Rodriguez-Jimenez C, Laborda J, et al. Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways. Oncotarget. 2015;6(4):1920-31.
3. Wang J, Li J, Liu Y, et al. The role and therapeutic implication of CPTs in fatty acid oxidation and cancer progression. Am J Cancer Res. 2021;11(6):2477-94.
4. Rossi Sebastiano M, Konstantinidou G. Targeting long-chain acyl-CoA synthetases for cancer therapy. Int J Mol Sci. 2019;20(15):3656. doi: 10.3390/ijms20153656.
5. Munir R, Lisec J, Swinnen JV, Zaidi N. Too complex to fail? Targeting fatty acid metabolism for cancer therapy. Prog Lipid Res. 2022;85:101143. doi: 10.1016/j.plipres.2021.101143.
6. Smith S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J. 1994;8(15):1248-59.
7. Liu H, Huang WD, Yang J, et al. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int J Biochem Mol Biol. 2010;1(1):69-89.
8. Jones SF, Infante JR. Molecular pathways: fatty acid synthase. Clin Cancer Res. 2015;21(24):5434-8. doi: 10.1158/1078-0432.CCR-15-1220.
9. Menendez JA, Lupu R, Colomer R. Targeting fatty acid synthase: potential for therapeutic intervention in HER2/neu-overexpressing breast cancer. Drug News Perspect. 2005;18(6):375-85.
10. Nagy P, Vereb G, Mehta K, et al. Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2. J Cell Sci. 2002;115(22):4251-62.
11. Weinhouse S, Millerd G. Neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 1953;13(1):27-9.
12. Ookhtens M, Kannan R, Lyon I, Baker N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol. 1984;247(1 Pt 1):E146-53.
13. Menendez JA, Vellon L, Mehmi I, et al. Inhibition of fatty acid synthase suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci U S A. 2004;101(29):10715-20. doi: 10.1073/pnas.0403396101.
14. Ho TS, Ho YP, Wong WY, Chiu LC, Wong YS, Ooi VE. Fatty acid synthase inhibitors cerulenin and C75 retard growth and induce caspase-dependent apoptosis in human melanoma A-375 cells. Biomed Pharmacother. 2007;61(9):578-87. doi: 10.1016/j.biopha.2007.08.020.
15. Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene. 2005;24(1):39-46. doi: 10.1038/sj.onc.1208174.
16. Orita H, Coulter J, Tully E, et al. Inhibition of fatty acid synthase by C247 for lung cancer treatment [abstract]. Cancer Res. 2005;65(9 Suppl):3631.
17. Orita H, Coulter J, Tully E, et al. High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy. Cancer Biol Ther. 2010;10(6):549-54. doi: 10.4161/cbt.10.6.12727.
18. Orita H, Coulter J, Tully E, et al. Selective inhibition of fatty acid synthase for lung cancer treatment. Clin Cancer Res. 2007;13(24):7139-45. doi: 10.1158/1078-0432.CCR-07-1281.
19. Orita H, Coulter J, Tully E, Kuhajda FP, Gabrielson E. Inhibiting fatty acid synthase for chemoprevention of chemically induced lung tumors. Clin Cancer Res. 2008;14(12):2458-64. doi: 10.1158/1078-0432.CCR-07-2378.
20. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 2004;64(6):2070-5. doi: 10.1158/0008-5472.CAN-03-3645.
21. Chen LY, Wu DS, Shen YA. Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through the FASN/APP axis. J Lipid Res. 2024;65(11):100660. doi: 10.1016/j.jlr.2024.100660.
22. Vazquez MJ, Schweizer M, Ruhlman N, et al. Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the β-ketoacyl reductase reaction. FEBS J. 2008;275(6):1556-67. doi: 10.1111/j.1742-4658.2008.06318.x.
23. Rivkin A, Balducci E, Gibson T, et al. Discovery of β-ketoacyl reductase inhibitors from a focused library. Bioorg Med Chem Lett. 2006;16(18):4620-3.
24. Richardson RD, Smith JW. Elucidation of the mechanism of action of a fatty acid synthase inhibitor. Mol Cancer Ther. 2007;6(8):2120-6.
25. Kley JT, Mack J, Hamilton B, Scheuerer S, Redemann N. Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure. Bioorg Med Chem Lett. 2011;21(20):5924-7. doi: 10.1016/j.bmcl.2011.08.046.
26. Turrado C, Puig T, Ruiz-Sánchez E, et al. New synthetic inhibitors of fatty acid synthase with anticancer activity. J Med Chem. 2012;55(11):5013-23. doi: 10.1021/jm300215b.
27. Hardwicke MA, Rendina AR, Williams SP, et al. A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site. Nat Chem Biol. 2014;10(9):774-9. doi: 10.1038/nchembio.1603.
28. Oslob JD, Johnson RJ, Cai H, et al. Imidazopyridine-based fatty acid synthase inhibitors that show anti-HCV activity and in vivo target modulation. ACS Med Chem Lett. 2013;4(1):113-7. doi: 10.1021/ml300335r.
29. Falchook GS, Karp DD, Wang B, et al. First-in-human study of the fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine. 2021;34:100797. doi: 10.1016/j.eclinm.2021.100797.
30. Alwarawrah Y, Bagby S, Kauttu S, et al. Fasnall, a selective FASN inhibitor, shows potent antitumor activity in the MMTV-Neu model of HER2-positive breast cancer. Cell Chem Biol. 2016;23(6):678-88. doi: 10.1016/j.chembiol.2016.05.003.
31. Makowski K, Ciszewski A, Szalacinski M, et al. (−)-UB006: a new fatty acid synthase inhibitor without anorexic side effects. Eur J Med Chem. 2017;131:207-21. doi: 10.1016/j.ejmech.2017.02.053.
32. Lu T, Schubert C, Davis L, et al. Design and synthesis of bioavailable fatty acid synthase KR-domain inhibitors for cancer therapy. Bioorg Med Chem Lett. 2018;28(12):2159-64. doi: 10.1016/j.bmcl.2018.04.061.
33. Bunkoczi G, Pasta S, Khosla C, et al. Structural basis for different specificities of acyltransferases associated with human cytosolic and mitochondrial fatty acid synthases. Chem Biol. 2009;16(6):667-75. doi: 10.1016/j.chembiol.2009.04.011.
34. Viegas MF, Neves RPP, Ramos MJ, Fernandes PA. Modeling of human fatty acid synthase and in silico docking of ACP domain. J Phys Chem B. 2018;122(1):77-85. doi: 10.1021/acs.jpcb.7b09645.
35. Paiva P, Sousa SF, Ramos MJ, Fernandes PA. Understanding the catalytic machinery of the MAT domain of human FASN. ACS Catal. 2018;8(6):4860-72. doi: 10.1021/acscatal.8b00577.
36. Pappenberger G, Benz J, Gsell B, et al. Structure of the human fatty acid synthase KS-MAT didomain as a framework for inhibitor design. J Mol Biol. 2010;397(2):508-19. doi: 10.1016/j.jmb.2010.01.066.
37. Zeng XF, Jin SW, Zhang Y, et al. Discovery of novel FAS inhibitors based on KS domain structure. Bioorg Med Chem Lett. 2011;21(16):4742-4. doi: 10.1016/j.bmcl.2011.06.075.
38. Wang X, Lu T, Liu Y, et al. Novel fatty acid synthase inhibitors: design and evaluation. Bioorg Med Chem. 2009;17(5):1898-904. doi: 10.1016/j.bmc.2009.01.050.
39. Nisthul AA, Retnakumari AP, Anto RJ, Sadasivan C. In silico screening for FAS inhibitors. J Recept Signal Transduct Res. 2018;38(4):335-41. doi: 10.1080/10799893.2018.1511730.
40. Nisthul AA, Archana PR, Anto RJ, Sadasivan C. Virtual screening-based identification of novel FAS inhibitors. J Mol Graph Model. 2021;105:107903. doi: 10.1016/j.jmgm.2021.107903.
41. Fang H, Zhang Y, Li J, et al. d-Pantolactone derivatives as novel FAS inhibitors. Bioorg Med Chem. 2019;27(20):115069. doi: 10.1016/j.bmc.2019.115069.
42. Martin MW, Hoover K, Liu J, et al. Discovery of novel piperazines as FASN inhibitors. Bioorg Med Chem Lett. 2019;29(8):1001-6. doi: 10.1016/j.bmcl.2019.02.042.
43. Singh S, Paul S, Brás NF, Kundu CN, Karthikeyan C, Moorthy NSHN. Benzo[d]imidazole-5-carboxamide FAS inhibitors. Bioorg Chem. 2023;138:106658. doi: 10.1016/j.bioorg.2023.106658.
44. Singh S, Karthikeyan C, Moorthy NSHN. Recent advances in fatty acid synthase inhibitors. Mini Rev Med Chem. 2020;20(18):1820-37. doi: 10.2174/1389557520666200811100845.
45. Pemble CW 4th, Johnson LC, Kridel SJ, Lowther WT. Crystal structure of human FAS thioesterase inhibited by orlistat. Nat Struct Mol Biol. 2007;14(8):704-9. doi: 10.1038/nsmb1265.
46. Zhang W, Chakravarty B, Sakabe M, et al. Crystal structure of FAS thioesterase domain with fatty acyl adducts. Proc Natl Acad Sci U S A. 2011;108(38):15757-62. doi: 10.1073/pnas.1112334108.
47. Lupien LE, Kuang X, Skorobogatko Y, et al. An inhibitor of the FAS thioesterase domain with improved cytotoxicity. J Pharmacol Exp Ther. 2019;371(1):171-85. doi: 10.1124/jpet.119.258947.
48. Jubie S, Rajamanickam D, Shyamsundar S, et al. Novel fatty acid analogues as human FAS thioesterase inhibitors. Lett Drug Des Discov. 2015;12(6):485-91. doi: 10.2174/1570180812666141216210751.
49. Chakravarty B, Gu Z, Chirala SS, Wakil SJ, Quiocho FA. Human fatty acid synthase: structure and substrate selectivity of the TE domain. Proc Natl Acad Sci U S A. 2004;101(44):15567-72. doi: 10.1073/pnas.0406901101.
50. Sadowski MC, Pouwer RH, Gunter JH, Lubik AA, Quinn RJ, Nelson CC. The fatty acid synthase inhibitor triclosan in prostate cancer. Oncotarget. 2014;5(19):9362-81. doi: 10.18632/oncotarget.2433.
51. Sun D, Zhao T, Long K, Wu M, Zhang Z. Triclosan downregulates fatty acid synthase via microRNAs. Eur J Pharmacol. 2021;907:174261. doi: 10.1016/j.ejphar.2021.174261.
52. Beebe J, Liu Y, Zhang W, et al. Therapeutic activity of lansoprazole metabolite inhibiting FAS enoyl reductase. J Med Chem. 2022;65(20):13681-91. doi: 10.1021/acs.jmedchem.2c00642.
53. Hasan SMN, Kattligolu E, Schneider S, et al. Atomic model for the core-modifying region of human fatty acid synthase in complex with denifanstat. Nat Commun. 2023;14(1):3460. doi: 10.1038/s41467-023-39266-y.
54. Aquino IG, Silva MLA, Gomes NP, et al. Anticancer properties of the fatty acid synthase inhibitor TVB-3166. Arch Oral Biol. 2020;113:104707. doi: 10.1016/j.archoralbio.2020.104707.
55. Qu H, Wang Y, Li J, et al. A novel small-molecule fatty acid synthase inhibitor with antitumor activity. Eur J Med Chem. 2021;219:113407. doi: 10.1016/j.ejmech.2021.113407.
56. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010;6(4):551-62. doi: 10.2217/fon.10.11.
57. Abuzaid AS, Iskandar EY, Kurniati NF, Adnyana IK. Preventive effect on obesity of mangosteen (Garcinia mangostana L.) pericarp ethanolic extract by reduction of fatty acid synthase level in monosodium glutamate and high calorie diet induced male Wistar rats. Asian J Pharm Clin Res. 2016;9(3):257 260.
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