Details of the Drug

General Information of Drug (ID: DM3U7SZ)

• Drug Name: Romiplostim

Indication

Disease Entry	ICD 11	Status	REF
Thrombocytopenia	3B64	Approved	[1], [2]
Multiple myeloma	2A83	Phase 2	[3], [4], [5]
Myelodysplastic syndrome	2A37	Phase 2	[1], [6]

• Drug Type: Small molecular drug
• Sequence:
  >Thrombopoietin receptor binding domain amino acid sequence
  IEGPTLRQWLAARA
  >Amino acid sequence for Fc fusion compound
  MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV
  DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA
  KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD
  SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGIEGPTLR
  QWLAARAGGGGGGGGIEGPTLRQWLAARA
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 238.28
  Topological Polar Surface Area (xlogp); 2.5
  Rotatable Bond Count (rotbonds); 1
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 1
• Chemical Identifiers:
  Formula: C15H14N2O
  IUPAC Name: (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1H-indol-2-one
  Canonical SMILES: CC1=CC(=C(N1)/C=C\\2/C3=CC=CC=C3NC2=O)C
  InChI: InChI=1S/C15H14N2O/c1-9-7-10(2)16-14(9)8-12-11-5-3-4-6-13(11)17-15(12)18/h3-8,16H,1-2H3,(H,17,18)/b12-8-
  InChIKey: WUWDLXZGHZSWQZ-WQLSENKSSA-N
• Cross-matching ID:
  PubChem CID: 5329098
  ChEBI ID: CHEBI:91083
  CAS Number: 194413-58-6
  DrugBank ID: DB05332
  TTD ID: D01PZD

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Aryl hydrocarbon receptor (AHR)	TT037IE	AHR_HUMAN	Modulator	[4], [7]
Fibroblast growth factor receptor 1 (FGFR1)	TTRLW2X	FGFR1_HUMAN	Inhibitor	[8]
Platelet-derived growth factor receptor alpha (PDGFRA)	TT8FYO9	PGFRA_HUMAN	Inhibitor	[9]
Platelet-derived growth factor receptor beta (PDGFRB)	TTI7421	PGFRB_HUMAN	Inhibitor	[9]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Inhibitor	[10]
Thrombopoietin receptor (MPL)	TTIHYA4	TPOR_HUMAN	Modulator	[2]
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Inhibitor	[11]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[8]
VEGFR1 messenger RNA (VEGFR1 mRNA)	TT1VAUK	VGFR1_HUMAN	Inhibitor	[11]

Molecular Expression Atlas of This Drug

• The Studied Disease: Thrombocytopenia
• ICD Disease Classification: 3B64

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Tyrosine-protein kinase Kit (KIT)	DTT	KIT	2.06E-01	-0.1	-0.14
Vascular endothelial growth factor receptor 2 (KDR)	DTT	KDR	1.98E-01	0.11	0.2
Fibroblast growth factor receptor 1 (FGFR1)	DTT	FGFR1	4.79E-02	-0.03	-0.15
Platelet-derived growth factor receptor beta (PDGFRB)	DTT	PDGFRB	5.35E-10	0.36	0.89
VEGFR1 messenger RNA (VEGFR1 mRNA)	DTT	FLT1	1.64E-05	0.29	0.51

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Romiplostim (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Carfilzomib	DM48K0X	Major	Additive thrombogenic effects by the combination of Romiplostim and Carfilzomib.	Multiple myeloma [2A83]	[70]

References

• [1] 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: 6974).
• [2] 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
• [3] 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: 5056).
• [4] A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points. Br J Cancer. 2005 Oct 17;93(8):876-83.
• [5] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [6] Emerging drugs for idiopathic thrombocytopenic purpura in adults. Expert Opin Emerg Drugs. 2008 Jun;13(2):237-54.
• [7] SU5416, a VEGF Receptor Inhibitor and Ligand of the AHR, Represents a New Alternative for Immunomodulation
• [8] Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem. 2002 Dec 19;45(26):5687-93.
• [9] Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel... J Med Chem. 2003 Mar 27;46(7):1116-9.
• [10] Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg Med Chem. 2010 Feb 15;18(4):1482-96.
• [11] New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven a... J Med Chem. 2000 Jun 15;43(12):2310-23.
• [12] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [13] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [14] 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. (Target id: 1722).
• [15] A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis. Blood. 2006 Jun 1;107(11):4300-7.
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [17] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [18] Clinical pipeline report, company report or official report of Ikena Oncology.
• [19] ClinicalTrials.gov (NCT04069026) A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer. U.S. National Institutes of Health.
• [20] In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo. Mol Pharmacol. 2014 Nov;86(5):593-608.
• [21] 1'H-Indole-3'-Carbonyl-Thiazole-4-Carboxylic Acid Methyl Ester Blocked Human Glioma Cell Invasion via Aryl Hydrocarbon Receptor's Regulation of Cytoskeletal Contraction. Biomed Res Int. 2020 Oct 3;2020:2616930.
• [22] 6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression. Chem Biol Interact. 2018 May 25;288:83-90.
• [23] Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol. 2006 Jun;69(6):1871-8.
• [24] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [25] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [26] E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405.
• [27] Clinical pipeline report, company report or official report of Hutchison Medi Pharma.
• [28] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [29] Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res. 2013 Apr;28(4):899-911.
• [30] 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. (Target id: 1808).
• [31] AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012 Apr 15;72(8):2045-56.
• [32] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [33] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029917)
• [34] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [35] A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRalpha) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Mar;73(3):595-604.
• [36] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [37] The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations.Invest New Drugs.2015 Apr;33(2):300-9.
• [38] Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
• [39] National Cancer Institute Drug Dictionary (drug id 452042).
• [40] Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Jul;74(1):195-204.
• [41] Clinical pipeline report, company report or official report of MedImmune (2011).
• [42] RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
• [43] Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther.2008 Oct;7(10):3129-40.
• [44] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [45] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [46] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [47] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [48] Company report (Neuronova)
• [49] Biochemical characterization of TAK-593, a novel VEGFR/PDGFR inhibitor with a two-step slow binding mechanism. Biochemistry. 2011 Feb 8;50(5):738-51.
• [50] Bcr-Abl tyrosine kinase inhibitors: a patent review.Expert Opin Ther Pat. 2015 Apr;25(4):397-412.
• [51] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [52] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [53] 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. (Target id: 2185).
• [54] Clinical pipeline report, company report or official report of Turning Point Therapeutics.
• [55] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [56] National Cancer Institute Drug Dictionary (drug name Zeteletinib).
• [57] Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl)pyridine template. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1913-9.
• [58] 2011 Pipeline of Sirna Therapeutics.
• [59] The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
• [60] Design and structure-activity relationship of 3-benzimidazol-2-yl-1H-indazoles as inhibitors of receptor tyrosine kinases. Bioorg Med Chem Lett. 2006 Jul 1;16(13):3595-9.
• [61] Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and prelimina... Bioorg Med Chem Lett. 2007 Dec 1;17(23):6593-601.
• [62] Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors. J Med Chem. 2005 Mar 10;48(5):1610-9.
• [63] Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents. J Med Chem. 2004 Oct 21;47(22):5367-80.
• [64] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [65] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [66] Clinical pipeline report, company report or official report of Exelixis (2011).
• [67] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services
• [68] Emerging drugs for ovarian cancer. Expert Opin Emerg Drugs. 2008 Sep;13(3):523-36.
• [69] YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011 Jul;102(7):1374-80.
• [70] Cerner Multum, Inc. "Australian Product Information.".