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Plasmodium falciparum histone deacetylase 1

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Target id: 3072

Nomenclature: Plasmodium falciparum histone deacetylase 1

Abbreviated Name: PfHDAC1

Family: Chromatin modifying enzymes (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 449 HDAC1 histone deacetylase 1
Previous and Unofficial Names Click here for help
KDAC1 | PFI1260c
Database Links Click here for help
Alphafold
ChEMBL Target
PlasmoDB
UniProtKB
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
JX21108 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 8.4 pEC50 6
pEC50 8.4 (EC50 3.6x10-9 M) SYBR Green I assay (72 hours) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
JX21108 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 8.4 pEC50 6
pEC50 8.4 (EC50 4x10-9 M) SYBR Green I assay (72 hours) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
quisinostat Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 8.3 pEC50 6
pEC50 8.3 (EC50 5.2x10-9 M) SYBR Green I assay (72 hours) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
quisinostat Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 8.1 pEC50 6
pEC50 8.1 (EC50 7.1x10-9 M) SYBR Green I assay (72 hours) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
JX21108 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfNF54 Parasite gametocyte viability assay - - 7.4 – 8.2 pEC50 6
pEC50 8.2 (EC50 5.9x10-9 M) Parasite late stage (IV) gametocyte assay using luciferase reporter line [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
pEC50 7.4 (EC50 3.88x10-8 M) Parasite early stage (II) gametocyte assay using luciferase reporter line [6]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
compound 1u [PMID: 30245402] Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
JX35 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 8.9 pIC50 11
pIC50 8.9 (IC50 1.26x10-9 M) SYBR Green I assay (72h) [11]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
JX35 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 8.8 pIC50 11
pIC50 8.8 (IC50 1.61x10-9 M) SYBR Green I assay (72h) [11]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1u [PMID: 30245402] Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 8.4 pIC50 3
pIC50 8.4 (IC50 4x10-9 M) [3H]-hypoxanthine incorporation [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 2h [PMID: 30664827] Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 8.3 pIC50 8
pIC50 8.3 (IC50 5.2x10-9 M) [3H]-hypoxanthine incorporation [8]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
panobinostat Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pk Parasite growth inhibition assay - - 8.1 pIC50 2
pIC50 8.1 (IC50 9x10-9 M) [3H]-hypoxanthine incorporation (48h) [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
panobinostat Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 8.0 pIC50 4
pIC50 8.0 (IC50 1x10-8 M) [3H]-hypoxanthine incorporation [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
JX35 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfNF54 Parasite late stage (V) gametocyte assay - - 7.9 pIC50 11
pIC50 7.9 (IC50 1.242x10-8 M) [11]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfTM90C2B Parasite growth inhibition assay - - 7.9 pIC50 9
pIC50 7.9 (IC50 1.326x10-8 M) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf7G8 Parasite growth inhibition assay - - 7.8 pIC50 9
pIC50 7.8 (IC50 1.436x10-8 M) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
JX35 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfNF54 Parasite early stage (II) gametocyte assay - - 7.8 pIC50 11
pIC50 7.8 (IC50 1.583x10-8 M) [11]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 7.8 pIC50 9
pIC50 7.8 (IC50 1.75x10-8 M) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfK1 Parasite growth inhibition assay - - 7.7 pIC50 9
pIC50 7.7 (IC50 1.905x10-8 M) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1u [PMID: 30245402] Small molecule or natural product Guide to Malaria Pharmacology Ligand Pb Parasite liver stage assay - - 7.6 pIC50 3
pIC50 7.6 (IC50 2.5x10-8 M) P. berghei Luciferase liver stage assay [3]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand PfNF54 Parasite growth inhibition assay - - 7.6 pIC50 9
pIC50 7.6 (IC50 2.527x10-8 M) [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
panobinostat Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfDd2 Parasite growth inhibition assay - - 7.5 pIC50 4
pIC50 7.5 (IC50 3x10-8 M) [3H]-hypoxanthine incorporation [4]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf3D7 Parasite growth inhibition assay - - 7.4 pIC50 9
pIC50 7.4 (IC50 4.1x10-8 M) SYBR Green assay [9]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
panobinostat Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfHB3 Parasite gametocyte viability assay - - 6.9 pIC50 10
pIC50 6.9 (IC50 1.18x10-7 M) AlamarBlue viability assay [10]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
panobinostat Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfDd2 Parasite gametocyte viability assay - - 6.8 pIC50 10
pIC50 6.8 (IC50 1.48x10-7 M) AlamarBlue viability assay [10]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
FNDR-20123 Small molecule or natural product Guide to Malaria Pharmacology Ligand Pf Parasite dual gamete formation assay (DGFA) - - 6.7 pIC50 9
pIC50 6.7 (IC50 1.9x10-7 M) Activity against male gametocytes. IC50 values of 190 nM for male and  > 5 µM for female gametocytes [9]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
panobinostat Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf3D7 Parasite gametocyte viability assay - - 6.0 pIC50 10
pIC50 6.0 (IC50 9.35x10-7 M) AlamarBlue viability assay [10]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Malaria Pharmacology Comments
The histone deacetylase (HDAC) family of enzymes are involved in the post-translational modification of histones by removal of acetyl groups from lysine residues. Removal of the acetyl groups facilitates tighter packing of chromatin (heterochromatin formation) leading to transcriptional repression. In humans, the 18 members of the HDAC family have been classified in to five subfamilies based on phylogenetic comparison with yeast homologues (see our HDACs Concise family page for more details). A recent review and analysis of the P. falciparum genome confirmed and classified the five known HDACs for this species of the parasite and identified a novel putative HDAC [7]:
Class I contains PfHDAC1
Class II contains PfHDA1 and PfHDA2
Class III contains the sirtuin-like PfSir2A and PfSir2B
PfCHD1 is a novel unclassified HDAC
This family of enzymes has been shown to be involved in the regulation of a number of processes during development of the malaria parasite including schizogony, gemetocytogenesis , antigenic variation and hepatocyte invasion.
HDACs have been identified as attractive molecular targets in the search for novel mechanisms to treat cancer and several small molecule HDAC inhibitors are already approved for clinical use. HDAC inhibitors have also emerged as potential therapies in a number of other disesases including malaria [1,4-5].

References

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1. Andrews KT, Tran TN, Lucke AJ, Kahnberg P, Le GT, Boyle GM, Gardiner DL, Skinner-Adams TS, Fairlie DP. (2008) Potent antimalarial activity of histone deacetylase inhibitor analogues. Antimicrob Agents Chemother, 52 (4): 1454-61. [PMID:18212103]

2. Chua MJ, Arnold MS, Xu W, Lancelot J, Lamotte S, Späth GF, Prina E, Pierce RJ, Fairlie DP, Skinner-Adams TS et al.. (2017) Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth. Int J Parasitol Drugs Drug Resist, 7 (1): 42-50. [PMID:28107750]

3. Diedrich D, Stenzel K, Hesping E, Antonova-Koch Y, Gebru T, Duffy S, Fisher G, Schöler A, Meister S, Kurz T et al.. (2018) One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites. Eur J Med Chem, 158: 801-813. [PMID:30245402]

4. Engel JA, Jones AJ, Avery VM, Sumanadasa SD, Ng SS, Fairlie DP, Skinner-Adams T, Andrews KT. (2015) Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites. Int J Parasitol Drugs Drug Resist, 5 (3): 117-26. [PMID:26199860]

5. Hansen FK, Sumanadasa SD, Stenzel K, Duffy S, Meister S, Marek L, Schmetter R, Kuna K, Hamacher A, Mordmüller B et al.. (2014) Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages. Eur J Med Chem, 82: 204-13. [PMID:24904967]

6. Huang Z, Li R, Tang T, Ling D, Wang M, Xu D, Sun M, Zheng L, Zhu F, Min H et al.. (2020) A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1. Cell Discov, 6 (1): 93. [PMID:33311461]

7. Kanyal A, Rawat M, Gurung P, Choubey D, Anamika K, Karmodiya K. (2018) Genome-wide survey and phylogenetic analysis of histone acetyltransferases and histone deacetylases of Plasmodium falciparum. FEBS J, 285 (10): 1767-1782. [PMID:29284196]

8. Mackwitz MKW, Hesping E, Antonova-Koch Y, Diedrich D, Woldearegai TG, Skinner-Adams T, Clarke M, Schöler A, Limbach L, Kurz T et al.. (2019) Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity. ChemMedChem, 14 (9): 912-926. [PMID:30664827]

9. Potluri V, Shandil RK, Gavara R, Sambasivam G, Campo B, Wittlin S, Narayanan S. (2020) Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria. Malar J, 19 (1): 365. [PMID:33046062]

10. Sun W, Tanaka TQ, Magle CT, Huang W, Southall N, Huang R, Dehdashti SJ, McKew JC, Williamson KC, Zheng W. (2014) Chemical signatures and new drug targets for gametocytocidal drug development. Sci Rep, 4: 3743. [PMID:24434750]

11. Wang M, Tang T, Li R, Huang Z, Ling D, Zheng L, Ding Y, Liu T, Xu W, Zhu F et al.. (2022) Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety. J Med Chem, 65 (5): 4156-4181. [PMID:35175762]

How to cite this page

Chromatin modifying enzymes (Plasmodium spp.): Plasmodium falciparum histone deacetylase 1. Last modified on 30/03/2022. Accessed on 02/07/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3072.