Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4EB85)

• DTT Name: Cholesterol 24-hydroxylase (CYP46A1)
• Synonyms: Cytochrome P450 46A1; CYP46; Cholesterol 24S-hydroxylase; Cholesterol 24-monooxygenase; CH24H
• Gene Name: CYP46A1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: CP46A_HUMAN
• TTD ID: T33641
• EC Number: EC 1.14.14.25
• Sequence:
  MSPGLLLLGSAVLLAFGLCCTFVHRARSRYEHIPGPPRPSFLLGHLPCFWKKDEVGGRVL
  QDVFLDWAKKYGPVVRVNVFHKTSVIVTSPESVKKFLMSTKYNKDSKMYRALQTVFGERL
  FGQGLVSECNYERWHKQRRVIDLAFSRSSLVSLMETFNEKAEQLVEILEAKADGQTPVSM
  QDMLTYTAMDILAKAAFGMETSMLLGAQKPLSQAVKLMLEGITASRNTLAKFLPGKRKQL
  REVRESIRFLRQVGRDWVQRRREALKRGEEVPADILTQILKAEEGAQDDEGLLDNFVTFF
  IAGHETSANHLAFTVMELSRQPEIVARLQAEVDEVIGSKRYLDFEDLGRLQYLSQVLKES
  LRLYPPAWGTFRLLEEETLIDGVRVPGNTPLLFSTYVMGRMDTYFEDPLTFNPDRFGPGA
  PKPRFTYFPFSLGHRSCIGQQFAQMEVKVVMAKLLQRLEFRLVPGQRFGLQEQATLKPLD
  PVLCTLRPRGWQPAPPPPPC
• Function: Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation. By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning. Further hydroxylates cholesterol derivatives and hormone steroids on both the ring and side chain of these molecules, converting them into active oxysterols involved in lipid signaling and biosynthesis. Acts as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2 and NR1H3 receptors shown to promote neurogenesis in developing brain. May also catalyze the oxidative metabolism of xenobiotics, such as clotrimazole. P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain.
• KEGG Pathway: Primary bile acid biosynthesis (hsa00120)
• Reactome Pathway: Endogenous sterols (R-HSA-211976)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TAK-935	DMOZAMN	Dravet syndrome	8A61.11	Phase 2	[1]

10 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID25514969-Compound-10	DME0XS4	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-11	DMUPL0W	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-12	DMOE5N0	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-13	DMQB03U	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-8	DM2NVLZ	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-9	DMAEZB1	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-Figure2-2	DMC6S0W	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-Figure2-3	DMUYVOP	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-Figure2-4	DMXSAN7	N. A.	N. A.	Patented	[2]
PMID25514969-Compound-Figure3	DM7D12Y	N. A.	N. A.	Patented	[2]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Cholesterol 24-hydroxylase (CYP46A1) DME Info
• Gene Name: CYP46A1

4 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dextromethorphan	DMUDJZM	Allergic rhinitis	CA08.0	Approved	[3]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[3]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[3]
Testosterone cypionate	DMC1TEV	N. A.	N. A.	Approved	[3]

1 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ANW-32821	DMMJOZD	N. A.	N. A.	Phase 2	[4]

1 Discontinued Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Phenacetin	DMRQAM0	Analgesia	MB40.8	Withdrawn from market	[3]

References

• [1] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040983)
• [2] Imidazo[1,2-a]pyridines as cholesterol 24-hydroxylase (CYP46A1) inhibitors: a patent evaluation (WO2014061676).Expert Opin Ther Pat. 2015 Mar;25(3):373-7.
• [3] Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003 Dec 9;42(48):14284-92.
• [4] Cholesterol-metabolizing cytochromes P450. Drug Metab Dispos. 2006 Apr;34(4):513-20.