Details of the Drug Combination

General Information of Drug Combination (ID: DCTV84M)

• Drug Combination Name: Dorsomorphin + IMD-0354
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Dorsomorphin (DMKYXJW): Small molecular drug
  IMD-0354 (DMOFSLE): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SU-DIPG-XIII
  Zero Interaction Potency (ZIP) Score: 4.593
  Bliss Independence Score: 11.633
  Loewe Additivity Score: 7.168
  LHighest Single Agent (HSA) Score: 5.31

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dorsomorphin

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

Dorsomorphin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
AMP-activated protein kinase (AMPK)	TTLAFZV	AAPK1_HUMAN; AAKB1_HUMAN; AAKG1_HUMAN	Inhibitor	[5]

Dorsomorphin Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bone morphogenetic protein receptor type-1B (BMPR1B)	OTGFN0OD	BMR1B_HUMAN	Increases Expression	[6]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Increases Expression	[7]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[8]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[8]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[7]
Bone morphogenetic protein receptor type-1A (BMPR1A)	OTQOA4ZH	BMR1A_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[8]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Increases Phosphorylation	[7]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[7]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Decreases Expression	[10]
5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1)	OT7TNF0L	AAPK1_HUMAN	Decreases Expression	[7]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[8]
Endoplasmic reticulum membrane sensor NFE2L1 (NFE2L1)	OT1QHOS2	NF2L1_HUMAN	Decreases Expression	[10]
Methylcytosine dioxygenase TET2 (TET2)	OTKKT03T	TET2_HUMAN	Decreases Expression	[7]
Hemojuvelin (HJV)	OT4235J2	RGMC_HUMAN	Decreases Expression	[6]
Forkhead box protein P3 (FOXP3)	OTA9Z9OC	FOXP3_HUMAN	Decreases Expression	[7]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Decreases Lipidation	[11]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[12]
Transferrin receptor protein 2 (TFR2)	OTMYCCEO	TFR2_HUMAN	Decreases Expression	[6]
Krueppel-like factor 2 (KLF2)	OTIP1UFX	KLF2_HUMAN	Decreases Expression	[13]

Indication(s) of IMD-0354

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Phase 1	[3]

IMD-0354 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Inhibitor of nuclear factor kappa-B kinase beta (IKKB)	TTJ3E9X	IKKB_HUMAN	Inhibitor	[14]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] 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: 4907).
• [3] Activation of histamine H4 receptor inhibits TNFalpha/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells. Apoptosis. 2014 Dec;19(12):1702-11.
• [4] Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation. Autophagy. 2016 Nov;12(11):2085-2097. doi: 10.1080/15548627.2016.1226733. Epub 2016 Sep 14.
• [5] The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular a... Bioorg Med Chem Lett. 2010 Nov 15;20(22):6394-9.
• [6] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.
• [7] Compound C induces autophagy and apoptosis in parental and hydroquinone-selected malignant leukemia cells through the ROS/p38 MAPK/AMPK/TET2/FOXP3 axis. Cell Biol Toxicol. 2020 Aug;36(4):315-331. doi: 10.1007/s10565-019-09495-3. Epub 2020 Jan 3.
• [8] p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells. Toxicol Appl Pharmacol. 2013 Feb 15;267(1):113-24. doi: 10.1016/j.taap.2012.12.016. Epub 2012 Dec 27.
• [9] Acute exposure to resveratrol inhibits AMPK activity in human skeletal muscle cells. Diabetologia. 2012 Nov;55(11):3051-60. doi: 10.1007/s00125-012-2691-1. Epub 2012 Aug 17.
• [10] Metformin leads to accumulation of reactive oxygen species by inhibiting the NFE2L1 expression in human hepatocellular carcinoma cells. Toxicol Appl Pharmacol. 2021 Jun 1;420:115523. doi: 10.1016/j.taap.2021.115523. Epub 2021 Apr 8.
• [11] -amanitin induces autophagy through AMPK-mTOR-ULK1 signaling pathway in hepatocytes. Toxicol Lett. 2023 Jul 1;383:89-97. doi: 10.1016/j.toxlet.2023.06.004. Epub 2023 Jun 16.
• [12] A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
• [13] Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype. Cardiovasc Res. 2010 Feb 1;85(3):514-9. doi: 10.1093/cvr/cvp337. Epub 2009 Oct 8.
• [14] I B kinase beta inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma. Clin Exp Allergy. 2011 Jan;41(1):104-15.