Nitisinone

Summary

Nitisinone (CHEMBL1337) is an approved small-molecule EC 1.13.11.27 (4-hydroxyphenylpyruvate dioxygenase) inhibitor (ATC A16AX04) targeting HPD; indicated across 3 conditions including tyrosinemia and alkaptonuria.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: A16AX04
• Targets: 1 (HPD)
• Indications: 3 conditions
• Clinical trials: 16
• Chemistry: 329.23 Da · C14H10F3NO5

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1337
Name	Nitisinone
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	115355
ChEBI	CHEBI:50378
ATC	A16AX04
Molecular formula	C14H10F3NO5
Molecular weight	329.23
InChIKey	OUBCNLGXQFSTLU-UHFFFAOYSA-N

SMILES: C1CC(=O)C(C(=O)C1)C(=O)C2=C(C=C(C=C2)C(F)(F)F)[N+](=O)[O-]

IUPAC name: 2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione

ChEBI definition: A cyclohexanone that is cyclohexane-1,3-dione substituted at position 2 by a 2-nitro-4-(trifluoromethyl)benzoyl group. It is used in the treatment of hereditary tyrosinemia type 1.

Pharmacological roles (ChEBI): EC 1.13.11.27 (4-hydroxyphenylpyruvate dioxygenase) inhibitor.

Also known as: Nitisinona, Nitisinone, Nityr, Orfadin, SC-0735, NITISINONE, SID174007248, NitisinoneÊ, NitisinoneÂ

Patent coverage: 483 distinct patent families (1,497 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,198 (80%) 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
HPD	4-hydroxyphenylpyruvate dioxygenase	Inhibition	7.4	1%	P32754

Broader ChEMBL bioactivity targets: 3 (assay-derived). Sample: 4-hydroxyphenylpyruvate dioxygenase, 4-hydroxyphenylpyruvate dioxygenase, 4-hydroxyphenylpyruvate dioxygenase.

Bioactivity

ChEMBL activities: 4 potent at pChembl ≥ 5 of 4 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
HPD	7.43	Ki	37	nM	CHEMBL_ACT_15095073
P32755	7.4	IC50	40	nM	CHEMBL_ACT_18228759
P32755	7.4	IC50	40	nM	CHEMBL_ACT_18228771
Q02110	7.4	IC50	40	nM	CHEMBL_ACT_229395

Target pathways

Aggregated over 1 target gene(s): HPD.

Top Reactome pathways

1 total, by targets touching each:

Pathway	Targets	Genes
Tyrosine catabolism	1	HPD

Dominant GO biological processes

GO term	Targets
L-phenylalanine catabolic process	1
L-tyrosine catabolic process	1
aromatic amino acid metabolic process	1

Indications & clinical

Indications

3 indications (1 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
tyrosinemia	4	MONDO:0004741	MONDO:0004741
alkaptonuria	3	MONDO:0008753	MONDO:0008753
albinism	1	MONDO:0043209	MONDO:0043209

Clinical trials

Total trials: 16.

Phase distribution

Phase	Trials
PHASE1	6
Not specified	4
PHASE3	2
PHASE2	2
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01390077	PHASE2/PHASE3	COMPLETED	Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
NCT01916382	PHASE3	UNKNOWN	Suitability of Nitisinone in Alkaptonuria 2
NCT02323529	PHASE3	COMPLETED	Efficacy and Safety of Once Daily Dosing Compared to Twice Daily Dosing of Nitisinone in HT-1
NCT00107783	PHASE2	COMPLETED	Long-Term Study of Nitisinone to Treat Alkaptonuria
NCT01828463	PHASE2	COMPLETED	Dose Response Study of Nitisinone in Alkaptonuria
NCT01838655	PHASE1/PHASE2	COMPLETED	Nitisinone for Type 1B Oculocutaneous Albinism
NCT01682538	PHASE1	COMPLETED	Bioequivalence of Orfadin Suspension Compared to Orfadin Capsules, and the Effect of Food on the Bioavailability of the Suspension
NCT01734889	PHASE1	COMPLETED	Taste and Palatability of Orfadin Suspension
NCT01857362	PHASE1	COMPLETED	Bioequivalence of Orfadin 20 mg Compared to Orfadin 10 mg Capsules.
NCT02750332	PHASE1	COMPLETED	Bioavailability Food-Effect Study of an Oral Nitisinone Formulation to Treat Hereditary Tyrosinemia (HT-1)
NCT02750345	PHASE1	COMPLETED	Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1)
NCT02750709	PHASE1	COMPLETED	Bioequivalence Study of Two Nitisinone Formulations Compared to Orfadin
NCT00031161	Not specified	COMPLETED	Prevention of Dichloroacetate Toxicity
NCT02320084	Not specified	COMPLETED	Long Term Safety Study of Orfadin Treatment in HT-1 Patients in Standard Clinical Care
NCT04113772	Not specified	UNKNOWN	Bio Equivalency 20 Mgm Orfadin and 20 Mgm of Nitisonine
NCT06227429	Not specified	WITHDRAWN	A Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in HT-1 Patients

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).