Details of the Drug

General Information of Drug (ID: DM21WBH)

• Drug Name: MK-2461
• Synonyms: MK 2461

Indication

Disease Entry	ICD 11	Status	REF
Alzheimer disease	8A20	Phase 1/2	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 495.6
  Topological Polar Surface Area (xlogp); 1.2
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 9
• Chemical Identifiers:
  Formula: C24H25N5O5S
  IUPAC Name: 14-[[[(2R)-1,4-dioxan-2-yl]methyl-methylsulfamoyl]amino]-5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene
  Canonical SMILES: CN1C=C(C=N1)C2=CC3=C(C=CC4=C(C3=O)C=C(C=C4)NS(=O)(=O)N(C)C[C@@H]5COCCO5)N=C2
  InChI: InChI=1S/C24H25N5O5S/c1-28-13-18(12-26-28)17-9-22-23(25-11-17)6-4-16-3-5-19(10-21(16)24(22)30)27-35(31,32)29(2)14-20-15-33-7-8-34-20/h3-6,9-13,20,27H,7-8,14-15H2,1-2H3/t20-/m1/s1
  InChIKey: JGEBLDKNWBUGRZ-HXUWFJFHSA-N
• Cross-matching ID:
  PubChem CID: 44137946
  CAS Number: 917879-39-1
  TTD ID: D00DRL

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
BDNF/NT-3 growth factors receptor (TrkB)	TTKN7QR	NTRK2_HUMAN	Inhibitor	[1]
Fibroblast growth factor receptor 1 (FGFR1)	TTRLW2X	FGFR1_HUMAN	Inhibitor	[1]
Fibroblast growth factor receptor 2 (FGFR2)	TTGJVQM	FGFR2_HUMAN	Inhibitor	[1]
Fibroblast growth factor receptor 3 (FGFR3)	TTST7KB	FGFR3_HUMAN	Inhibitor	[1]
Fms-like tyrosine kinase 3 (FLT-3)	TTGJCWZ	FLT3_HUMAN	Inhibitor	[1]
Macrophage-stimulating protein receptor (RON)	TTBQ3OC	RON_HUMAN	Inhibitor	[1]
NT-3 growth factor receptor (TrkC)	TTXABCW	NTRK3_HUMAN	Inhibitor	[1]
Platelet-derived growth factor receptor beta (PDGFRB)	TTI7421	PGFRB_HUMAN	Inhibitor	[1]
Proto-oncogene c-Met (MET)	TTNDSF4	MET_HUMAN	Inhibitor	[1]
Tyrosine-protein kinase Mer (MERTK)	TTO7LKR	MERTK_HUMAN	Inhibitor	[1]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[1]
Vascular endothelial growth factor receptor 3 (FLT-4)	TTDCBX5	VGFR3_HUMAN	Inhibitor	[1]
VEGFR1 messenger RNA (VEGFR1 mRNA)	TT1VAUK	VGFR1_HUMAN	Inhibitor	[1]

Molecular Expression Atlas of This Drug

• The Studied Disease: Alzheimer disease
• ICD Disease Classification: 8A20

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
NT-3 growth factor receptor (TrkC)	DTT	NTRK3	7.06E-04	-0.14	-0.43
Vascular endothelial growth factor receptor 2 (KDR)	DTT	KDR	1.98E-01	0.11	0.2
Fibroblast growth factor receptor 3 (FGFR3)	DTT	FGFR3	5.83E-03	0.08	0.1
Fibroblast growth factor receptor 1 (FGFR1)	DTT	FGFR1	4.79E-02	-0.03	-0.15
Tyrosine-protein kinase Mer (MERTK)	DTT	MERTK	5.86E-04	0.3	0.47
Proto-oncogene c-Met (MET)	DTT	MET	1.08E-03	-0.24	-0.4
BDNF/NT-3 growth factors receptor (TrkB)	DTT	NTRK2	3.06E-01	-0.15	-0.31
Platelet-derived growth factor receptor beta (PDGFRB)	DTT	PDGFRB	5.35E-10	0.36	0.89
Fibroblast growth factor receptor 2 (FGFR2)	DTT	FGFR2	4.82E-01	-0.03	-0.2
Fms-like tyrosine kinase 3 (FLT-3)	DTT	FLT3	2.11E-01	-0.05	-0.16
Vascular endothelial growth factor receptor 3 (FLT-4)	DTT	FLT4	6.00E-01	-0.04	-0.23
Macrophage-stimulating protein receptor (RON)	DTT	MST1R	1.59E-01	-0.03	-0.23
VEGFR1 messenger RNA (VEGFR1 mRNA)	DTT	FLT1	1.64E-05	0.29	0.51

References

• [1] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [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. (Target id: 1816).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services
• [4] 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.
• [5] Clinical pipeline report, company report or official report of Hutchison Medi Pharma.
• [6] Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45.
• [7] Company report (Medigen)
• [8] Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20.
• [9] Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006.
• [10] 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: 1814).
• [11] Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
• [12] 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.
• [13] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [14] Clinical pipeline report, company report or official report of Exelixis (2011).
• [15] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [17] Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC. Cancer Discov. 2020 Aug;10(8):1194-1209.
• [18] 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: 1815).
• [19] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [20] Beperminogene perplasmid for the treatment of critical limb ischemia. Expert Rev Cardiovasc Ther. 2014 Oct;12(10):1145-56.
• [21] 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: 7948).
• [22] Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem. 2002 Dec 19;45(26):5687-93.
• [23] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [24] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [25] 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.
• [26] Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res. 2013 Apr;28(4):899-911.
• [27] 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).
• [28] 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.
• [29] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [30] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [31] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [32] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849.
• [33] Clinical pipeline report, company report or official report of Ono Pharmaceutical.
• [34] National Cancer Institute Drug Dictionary (drug name RXDX106).
• [35] The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI Insight. 2016 Mar;1(3):e85630.
• [36] National Cancer Institute Drug Dictionary (drug name PF-07265807).
• [37] A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity. Front Oncol. 2020 Dec 7;10:598477.
• [38] The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12.
• [39] G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. Blood. 2014 Apr 3;123(14):2209-19.
• [40] MerTK as a therapeutic target in glioblastoma. Neuro Oncol. 2018 Jan 10;20(1):92-102.
• [41] UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Mol Cancer Ther. 2013 Nov;12(11):2367-77.
• [42] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [43] Keratinocyte growth factor. Expert Opin Biol Ther. 2009 Jun;9(6):779-87.
• [44] Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
• [45] Company report (Eli Lilly) (drug: LY2874455)
• [46] National Cancer Institute Drug Dictionary (drug id 751593).
• [47] Corrigendum to 'Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models' [Eur J Cancer 61 (2016) 20-28]. Eur J Cancer. 2017 Jan;70:156.
• [48] 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.
• [49] 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.
• [50] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [51] National Cancer Institute Drug Dictionary (drug id 452042).
• [52] Company report (Neuronova)
• [53] 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.
• [54] RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
• [55] Bcr-Abl tyrosine kinase inhibitors: a patent review.Expert Opin Ther Pat. 2015 Apr;25(4):397-412.
• [56] 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: 1807).
• [57] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [58] Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with ... Blood. 2008 Jun 15;111(12):5663-71.
• [59] 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.
• [60] 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.
• [61] 2011 Pipeline of Sirna Therapeutics.
• [62] The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
• [63] 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.
• [64] 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.
• [65] 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.
• [66] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [67] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [68] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [69] Emerging drugs for ovarian cancer. Expert Opin Emerg Drugs. 2008 Sep;13(3):523-36.
• [70] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [71] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [72] In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia. PLoS One. 2020 Dec 28;15(12):e0244368.
• [73] Clinical pipeline report, company report or official report of Genentech (2011).