Details of the Drug Combination

General Information of Drug Combination (ID: DCWZHL8)

• Drug Combination Name: ACER-001 + Benzoic Acid
• Indication: Urea Cycle Disorders, Inborn; Status: Phase 1 [1]
• Component Drugs:
  ACER-001 (DM9HJFJ): N.A.
  Benzoic Acid (DMKB9FI): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ACER-001

Disease Entry	ICD 11	Status	REF
Maple-syrup-urine disease	5C50.D0	Investigative	[2]

Indication(s) of Benzoic Acid

Disease Entry	ICD 11	Status	REF
Alopecia areata	ED70.2	Approved	[3]
Dermatomyositis	4A41.0	Approved	[4]
Fungal infection	1F29-1F2F	Approved	[5]
Mycoses	1F2Z	Approved	[6]
Ornithine transcarbamylase deficiency	5C50.AY	Approved	[7]
Peyronie disease	N.A.	Investigative	[8]
Scleroderma	4A42	Investigative	[9]

Benzoic Acid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Ras-related protein Rab-9A (RAB9A)	TT958S6	RAB9A_HUMAN	Inhibitor	[12]

Benzoic Acid Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Sodium-coupled monocarboxylate transporter 2 (SLC5A12)	DTM301H	SC5AC_HUMAN	Substrate	[13]

Benzoic Acid Interacts with 34 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Increases Activity	[14]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Expression	[15]
Metallothionein-2 (MT2A)	OTHOACHD	MT2_HUMAN	Increases Expression	[10]
Metallothionein-1A (MT1A)	OTKBH52X	MT1A_HUMAN	Increases Expression	[10]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Increases Expression	[11]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[11]
Glutathione reductase, mitochondrial (GSR)	OTM2TUYM	GSHR_HUMAN	Increases Expression	[11]
Ferritin light chain (FTL)	OTYQA8A6	FRIL_HUMAN	Increases Expression	[11]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[11]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Expression	[11]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Increases Expression	[11]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[11]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Increases Expression	[11]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Expression	[11]
NADP-dependent malic enzyme (ME1)	OTSVEUQE	MAOX_HUMAN	Increases Expression	[11]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[11]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Increases Expression	[11]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Expression	[11]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Expression	[11]
Prostaglandin reductase 1 (PTGR1)	OTMAR351	PTGR1_HUMAN	Increases Expression	[11]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[11]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases Activity	[16]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Activity	[17]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[18]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[19]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Tyrosine-protein phosphatase non-receptor type 2 (PTPN2)	OTV4VJGE	PTN2_HUMAN	Decreases Activity	[20]
Tyrosine-protein phosphatase non-receptor type 1 (PTPN1)	OTO4ZVIA	PTN1_HUMAN	Decreases Activity	[20]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[18]
Low molecular weight phosphotyrosine protein phosphatase (ACP1)	OTJ9CKLU	PPAC_HUMAN	Decreases Activity	[20]
Solute carrier family 15 member 1 (SLC15A1)	OT1P16B5	S15A1_HUMAN	Affects Binding	[21]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Chemical Synthesis	[22]
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Increases Chemical Synthesis	[23]
Monocarboxylate transporter 1 (SLC16A1)	OTW1UTZ7	MOT1_HUMAN	Increases Uptake	[24]

References

• [1] ClinicalTrials.gov (NCT02111200) Comparative Efficacy of Phenylbutyrate (PBA) vs. Benzoate in Urea Cycle Disorders
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Benzoic acid and its derivatives as naturally occurring compounds in foods and as additives: Uses, exposure, and controversy. Crit Rev Food Sci Nutr. 2017 Sep 22;57(14):3084-3103.
• [4] Benzoic acid production via cascade biotransformation and coupled fermentation-biotransformation. Biotechnol Bioeng. 2020 Aug;117(8):2340-2350.
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4565).
• [6] Synergistic effect of antioxidant system and osmolyte in hydrogen sulfide and salicylic acid crosstalk-induced heat tolerance in maize (Zea mays L.) seedlings. Plant Signal Behav. 2015;10(9):e1051278.
• [7] Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol. 2003;7(3):115-21.
• [8] Safety Assessment of Benzyl Alcohol, Benzoic Acid and its Salts, and Benzyl Benzoate. Int J Toxicol. 2017 Nov/Dec;36(3_suppl):5S-30S.
• [9] The intracellular chloride channel 4 (CLIC4) activates systemic sclerosis fibroblasts. Rheumatology (Oxford). 2021 Sep 1;60(9):4395-4400.
• [10] A new in vitro method for identifying chemical sensitizers combining peptide binding with ARE/EpRE-mediated gene expression in human skin cells. Cutan Ocul Toxicol. 2010 Sep;29(3):171-92.
• [11] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [13] Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10(1):193-9.
• [14] Benzoic acid derivatives induce recovery of catalytic activity in the partially inactive Met208Lys mutant of human glutathione transferase A1-1. J Mol Biol. 1999 May 14;288(4):787-800.
• [15] A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide. 2005 Mar;12(2):97-104.
• [16] Differentiation between stoichiometric and anticatalytic antioxidant properties of benzoic acid analogues: a structure/redox potential relationship study. Chem Biol Interact. 2013 Nov 25;206(2):194-203.
• [17] In vitro effects of quercetin on oxidative stress mediated in human erythrocytes by benzoic acid and citric acid. Folia Biol (Krakow). 2014;62(1):59-66.
• [18] Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo. Cancer Res. 2016 Feb 1;76(3):652-63. doi: 10.1158/0008-5472.CAN-14-3558. Epub 2015 Jun 18.
• [19] Analysis of interleukin-1alpha (IL-1alpha) and interleukin-8 (IL-8) expression and release in in vitro reconstructed human epidermis for the prediction of in vivo skin irritation and/or sensitization. Toxicol In Vitro. 2003 Jun;17(3):311-21. doi: 10.1016/s0887-2333(03)00019-5.
• [20] Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells. Eur J Med Chem. 2014 Jan;71:112-27. doi: 10.1016/j.ejmech.2013.11.001. Epub 2013 Nov 11.
• [21] Affinity and translocation relationships via hPEPT1 of H-X aa-Ser-OH dipeptides: evaluation of H-Phe-Ser-OH as a pro-moiety for ibuprofen and benzoic acid prodrugs. Eur J Pharm Biopharm. 2011 Feb;77(2):327-31. doi: 10.1016/j.ejpb.2010.12.009. Epub 2010 Dec 13.
• [22] Metabolism of N-nitrosobenzylmethylamine by human cytochrome P-450 enzymes. J Toxicol Environ Health A. 1999 Dec 10;58(7):397-411.
• [23] Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine. Chem Biol Interact. 2018 Sep 25;293:107-114.
• [24] Inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells. J Pharm Pharmacol. 2007 Nov;59(11):1515-9. doi: 10.1211/jpp.59.11.0008.