Givinostat

Summary

Givinostat (CHEMBL1213492) is an approved small-molecule EC 3.5.1.98 (histone deacetylase) inhibitor (ATC M09AX14) targeting HDAC2, HDAC3, and HDAC6; indicated across 9 conditions including duchenne muscular dystrophy and b-cell chronic lymphocytic leukemia.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: M09AX14
• Targets: 9 (HDAC2, HDAC3, HDAC6…)
• Indications: 9 conditions
• Clinical trials: 23
• Chemistry: 421.5 Da · C24H27N3O4

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1213492
Name	Givinostat
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	9804992
ChEBI	CHEBI:94187
ATC	M09AX14
Molecular formula	C24H27N3O4
Molecular weight	421.5
InChIKey	YALNUENQHAQXEA-UHFFFAOYSA-N

SMILES: CCN(CC)CC1=CC2=C(C=C1)C=C(C=C2)COC(=O)NC3=CC=C(C=C3)C(=O)NO

IUPAC name: [6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate

ChEBI definition: A member of the class of naphthalenes that is naphthalene substituted by ({[4-(hydroxycarbamoyl)phenyl]carbamoyl}oxy)methyl and (diethylamino)methyl groups at positions 2 and 6, respectively. It is a histone deacetylase inhibitor indicated for individuals diagnosed with Duchenne muscular dystrophy.

Pharmacological roles (ChEBI): EC 3.5.1.98 (histone deacetylase) inhibitor, anti-inflammatory agent, angiogenesis inhibitor, antineoplastic agent, apoptosis inducer.

Also known as: Givinostat, ITF 2357, ITF-2357, ITF2357, GIVINOSTAT, ITF2357 (GIVINOSTAT), ITF2357 (Givinostat), Givinostat hydrochloride

Parent form; salt/anhydrous children: CHEMBL6068400

Patent coverage: 1,137 distinct patent families (2,827 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 2,151 (76%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
HDAC2	histone deacetylase 2	Inhibition	7.25	3.1%	Q92769
HDAC3	histone deacetylase 3	Inhibition	7.68	95.1% (common-essential)	O15379
HDAC6	histone deacetylase 6	Inhibition	7.57	0%	Q9UBN7
HDAC8	histone deacetylase 8	Inhibition	7.41	4.9%	Q9BY41
HDAC9	histone deacetylase 9	Inhibition	6.41	0%	Q9UKV0
HDAC1	histone deacetylase 1	Inhibition	7.55	4.5%	Q13547
HDAC4	histone deacetylase 4	Inhibition	5.98	3.1%	P56524
HDAC5	histone deacetylase 5	Inhibition	6.22	0.5%	Q9UQL6
HDAC7	histone deacetylase 7	Inhibition	6.62	4.2%	Q8WUI4

Broader ChEMBL bioactivity targets: 12 (assay-derived). Sample: Histone deacetylase 3, Protein deacetylase HDAC6, Histone deacetylase 2, Histone deacetylase 3/Nuclear receptor corepressor 2 (HDAC3/NCoR2), Histone deacetylase 5, Histone deacetylase 7, Histone deacetylase 8, Histone deacetylase 1, Histone deacetylase 11, Histone deacetylase 4.

Bioactivity

ChEMBL activities: 34 potent at pChembl ≥ 5 of 34 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
HDAC1	8.7	Ki	2	nM	CHEMBL_ACT_15656400
HDAC1	8.7	Ki	2	nM	CHEMBL_ACT_3389946
HDAC3	8.52	Ki	3	nM	CHEMBL_ACT_15656380
HDAC2	8.52	Ki	3	nM	CHEMBL_ACT_15656390
HDAC2	8.52	Ki	3	nM	CHEMBL_ACT_3389947
HDAC3	8.52	Ki	3	nM	CHEMBL_ACT_3389948
HDAC6	8.38	Ki	4.2	nM	CHEMBL_ACT_15656473
HDAC6	8.38	Ki	4.2	nM	CHEMBL_ACT_3389951
HDAC6	7.85	IC50	14	nM	CHEMBL_ACT_24671870
HDAC6	7.64	IC50	23	nM	CHEMBL_ACT_23238889
HDAC6	7.46	IC50	35.02	nM	CHEMBL_ACT_23140972
HDAC1	7.46	IC50	35	nM	CHEMBL_ACT_24671848
HDAC8	7.41	Ki	39	nM	CHEMBL_ACT_15656429
HDAC8	7.41	Ki	39	nM	CHEMBL_ACT_3389953
HDAC6	7.36	IC50	44	nM	CHEMBL_ACT_19315171
HDAC1	7.16	IC50	70	nM	CHEMBL_ACT_23238869
HDAC1	6.88	IC50	133	nM	CHEMBL_ACT_22974813
HDAC3	6.87	IC50	136	nM	CHEMBL_ACT_22974815
HDAC7	6.62	Ki	240	nM	CHEMBL_ACT_15656455
HDAC7	6.62	Ki	240	nM	CHEMBL_ACT_3389952
HDAC11	6.54	IC50	287	nM	CHEMBL_ACT_22974788
HDAC2	6.53	IC50	293	nM	CHEMBL_ACT_22974814
HDAC6	6.51	IC50	312	nM	CHEMBL_ACT_22974789
HDAC10	6.48	IC50	331	nM	CHEMBL_ACT_22974790
HDAC9	6.41	Ki	390	nM	CHEMBL_ACT_15656463
HDAC9	6.41	Ki	390	nM	CHEMBL_ACT_3389954
HDAC9	6.29	IC50	512	nM	CHEMBL_ACT_22974791
HDAC7	6.28	IC50	524	nM	CHEMBL_ACT_22974792
HDAC5	6.27	IC50	532	nM	CHEMBL_ACT_22974818
HDAC5	6.22	Ki	600	nM	CHEMBL_ACT_15656446

Target pathways

Aggregated over 9 target gene(s): HDAC2, HDAC3, HDAC6, HDAC8, HDAC9, HDAC1, HDAC4, HDAC5, HDAC7.

Top Reactome pathways

71 total, by targets touching each:

Pathway	Targets	Genes
NOTCH1 Intracellular Domain Regulates Transcription	9	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
Constitutive Signaling by NOTCH1 PEST Domain Mutants	9	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	9	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
Notch-HLH transcription pathway	9	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	9	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
Regulation of PTEN gene transcription	5	HDAC1, HDAC2, HDAC3, HDAC5, HDAC7
HDACs deacetylate histones	4	HDAC1, HDAC2, HDAC3, HDAC8
p75NTR negatively regulates cell cycle via SC1	3	HDAC1, HDAC2, HDAC3
SUMOylation of chromatin organization proteins	3	HDAC1, HDAC2, HDAC4
Regulation of MECP2 expression and activity	3	HDAC1, HDAC2, HDAC3
STAT3 nuclear events downstream of ALK signaling	3	HDAC1, HDAC2, HDAC3
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	2	HDAC1, HDAC2
NoRC negatively regulates rRNA expression	2	HDAC1, HDAC2
Regulation of TP53 Activity through Acetylation	2	HDAC1, HDAC2
RNA Polymerase I Transcription Initiation	2	HDAC1, HDAC2
RUNX2 regulates osteoblast differentiation	2	HDAC3, HDAC6
MECP2 regulates neuronal receptors and channels	2	HDAC1, HDAC2
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	2	HDAC1, HDAC2
Potential therapeutics for SARS	2	HDAC1, HDAC2
Negative Regulation of CDH1 Gene Transcription	2	HDAC1, HDAC2
Factors involved in megakaryocyte development and platelet production	2	HDAC1, HDAC2
Regulation of endogenous retroelements by KRAB-ZFP proteins	2	HDAC1, HDAC2
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	2	HDAC1, HDAC2
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	HDAC1, HDAC2
NuRD complex assembly	2	HDAC1, HDAC2
Interaction of NuRD complexes with transcription factors	2	HDAC1, HDAC2
Transcription of E2F targets under negative control by DREAM complex	1	HDAC1
Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1	1	HDAC1
G0 and Early G1	1	HDAC1
PPARA activates gene expression	1	HDAC3

Dominant GO biological processes

GO term	Targets
chromatin organization	9
negative regulation of transcription by RNA polymerase II	8
negative regulation of DNA-templated transcription	8
positive regulation of transcription by RNA polymerase II	5
protein deacetylation	5
epigenetic regulation of gene expression	5
negative regulation of gene expression, epigenetic	5
negative regulation of macromolecule biosynthetic process	4
chromatin remodeling	3
positive regulation of cell population proliferation	3
response to xenobiotic stimulus	3
heterochromatin formation	3
circadian regulation of gene expression	3
positive regulation of intracellular estrogen receptor signaling pathway	3
negative regulation of apoptotic process	3

Indications & clinical

Indications

9 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
Duchenne muscular dystrophy	3	MONDO:0010679	MONDO:0010311
B-cell chronic lymphocytic leukemia	2	MONDO:0004948	EFO:0000095
plasma cell myeloma	2	MONDO:0009693	EFO:0001378
juvenile idiopathic arthritis	2	MONDO:0011429	EFO:0002609
Hodgkins lymphoma	1	MONDO:0004952	EFO:0000183
Crohn disease	1	MONDO:0005011	EFO:0000384
acquired polycythemia vera	1	MONDO:0009891	EFO:0002429

2 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 23.

Phase distribution

Phase	Trials
PHASE2	9
PHASE1	5
PHASE1/PHASE2	4
PHASE3	3
PHASE2/PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03373968	PHASE2/PHASE3	RECRUITING	Givinostat in Duchenne’s Muscular Dystrophy Long-term Safety and Tolerability Study
NCT05933057	PHASE3	RECRUITING	Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy
NCT06093672	PHASE3	RECRUITING	Study on Efficacy and Safety of Givinostat Versus Hydroxyurea in Patients With Polycythemia Vera
NCT02851797	PHASE3	COMPLETED	Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
NCT01761968	PHASE2	ACTIVE_NOT_RECRUITING	Long-term Study Evaluating the Effect of Givinostat in Patients With Chronic Myeloproliferative Neoplasms
NCT06769633	PHASE2	RECRUITING	Pharmacokinetics and Safety of Givinostat in DMD Patients Ages From at Least 2 Years to Less Then 6 Years Old
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00570661	PHASE2	COMPLETED	Open Label, Multicentre Trial to Assess Safety and Efficacy of ITF2357 in Active Systemic Juvenile Idiopathic Arthritis
NCT00606307	PHASE2	COMPLETED	Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases
NCT00792467	PHASE1/PHASE2	COMPLETED	Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin’s Lymphoma
NCT00792506	PHASE2	TERMINATED	Phase II Clinical Trial of ITF2357 In Patients With Relapsed/Refractory Multiple Myeloma
NCT00792740	PHASE1/PHASE2	TERMINATED	Effect of ITF2357 on Mucosal Healing in Patients With Moderate-to-severe Active Crohn’s Disease
NCT00792831	PHASE2	TERMINATED	Phase II Study of Histone-deacetylase Inhibitor ITF2357 in Refractory/Relapsed Lymphocytic Leukemia
NCT01261624	PHASE2	TERMINATED	Efficacy and Safety Dose Finding Study of Givinostat to Treat Polyarticular Course Juvenile Idiopathic Arthritis
NCT01761292	PHASE1/PHASE2	COMPLETED	A Study to Assess Safety/Tolerability, pk, Effects on Histology, Clinical Parameters of Givinostat in Children With DMD
NCT01901432	PHASE1/PHASE2	COMPLETED	A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera
NCT03238235	PHASE2	COMPLETED	Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Becker Muscular Dystrophy
NCT04821063	PHASE1	COMPLETED	Placebo-Corrected Effects of Therapeutic Dose (100 mg) and Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval
NCT05492318	PHASE1	COMPLETED	Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity
NCT05845567	PHASE1	COMPLETED	The Potential of Givinostat as DDI Victim in Co-administration P-gp Inhibitor (Part 2)
NCT05860114	PHASE1	COMPLETED	Givinostat and Metabolites Pharmacokinetics in Urine and Plasma (Part 3)
NCT06736223	PHASE1	COMPLETED	Pharmacokinetics, Safety and Tolerability of ITF2357 in Participants With Chronic Hepatic Impairment and With Normal Hepatic Function
NCT01557452	Not specified	TERMINATED	Open-Label Extension of the Dose Finding Study (DSC/08/2357/36) in Patients With Poly Juvenile Idiopathic Arthritis

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

96 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
BELINOSTAT	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
CELECOXIB	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
PANOBINOSTAT	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
PHENYLBUTANOIC ACID	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
ROMIDEPSIN	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
SODIUM PHENYLBUTYRATE	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
VORINOSTAT	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
ABEXINOSTAT	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
CAFFEIC ACID	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
CURCUMIN	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
ENTINOSTAT	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
PRACINOSTAT	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
TACEDINALINE	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
TUCIDINOSTAT	ChEMBL	Phase 3	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
AR-42	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
CHLOROGENIC ACID	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
DACINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
FIMEPINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
NANATINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
QUISINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
Pazopanib	PubChem	Approved	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9
RICOLINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8
BENDAMUSTINE	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC8
TINOSTAMUSTINE	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC8
CITARINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, HDAC8
BORTEZOMIB	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC3, HDAC6, HDAC8
MOCETINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC6, HDAC8
EBSELEN	ChEMBL	Phase 3	HDAC2, HDAC5, HDAC6, HDAC9
BUTYRIC ACID	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC8
DOMATINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC9
SODIUM BUTYRATE	ChEMBL	Phase 2	HDAC1, HDAC2, HDAC3, HDAC8
ATORVASTATIN	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC6
DAUNORUBICIN	ChEMBL	Phase 4 (approved)	HDAC1, HDAC6, HDAC8
LOVASTATIN	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2, HDAC6
BAICALEIN	ChEMBL	Phase 2	HDAC1, HDAC6, HDAC8
.gamma.-aminobutyric acid	PubChem	Approved	HDAC5, HDAC7, HDAC9
acetylcysteine	PubChem	Approved	HDAC5, HDAC7, HDAC9
Crizotinib	PubChem	Approved	HDAC1, HDAC2, HDAC6
VALPROIC ACID	ChEMBL	Phase 4 (approved)	HDAC1, HDAC2
MOLIBRESIB	ChEMBL	Phase 2	HDAC1, HDAC2
NICOXAMAT	ChEMBL	Phase 2	HDAC1, HDAC6
RESMINOSTAT	ChEMBL	Phase 2	HDAC1, HDAC6
Gefitinib	PubChem	Approved	HDAC5, HDAC9
Idelalisib	PubChem	Approved	HDAC1, HDAC6
ABAMETAPIR	ChEMBL	Phase 4 (approved)	HDAC6
ATALUREN	ChEMBL	Phase 4 (approved)	HDAC6
AXITINIB	ChEMBL	Phase 4 (approved)	HDAC6
BUFEXAMAC	ChEMBL	Phase 4 (approved)	HDAC6
EVANS BLUE FREE ACID	ChEMBL	Phase 4 (approved)	HDAC6
EXIFONE	ChEMBL	Phase 4 (approved)	HDAC1
FEBUXOSTAT	ChEMBL	Phase 4 (approved)	HDAC6
FLUPHENAZINE	ChEMBL	Phase 4 (approved)	HDAC6
GENTIAN VIOLET	ChEMBL	Phase 4 (approved)	HDAC6
INDOPROFEN	ChEMBL	Phase 4 (approved)	HDAC6
MARIBAVIR	ChEMBL	Phase 4 (approved)	HDAC6
MOMELOTINIB	ChEMBL	Phase 4 (approved)	HDAC1
MONOBENZONE	ChEMBL	Phase 4 (approved)	HDAC6
NITAZOXANIDE	ChEMBL	Phase 4 (approved)	HDAC6
PHENYL AMINOSALICYLATE	ChEMBL	Phase 4 (approved)	HDAC6
PIPERACETAZINE	ChEMBL	Phase 4 (approved)	HDAC6