Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DML4UMT)

• Drug Name: GW-8510 Drug Info

Indication

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[1]

• Cross-matching ID:
  PubChem CID: 3536
  ChEBI ID: CHEBI:95283
  TTD Drug ID: DML4UMT

Molecule-Related Drug Atlas

Drug(s) Targeting Cyclin A2 (CCNA2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[4]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[5]
aloisine A	DM5U1LN	Discovery agent	N.A.	Investigative	[6]
3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol	DMJZK40	Discovery agent	N.A.	Investigative	[5]
MERIOLIN 8	DM0E95B	Discovery agent	N.A.	Investigative	[7]
2,5-dichloro-N-p-tolylthiophene-3-sulfonamide	DMU5J8Y	Discovery agent	N.A.	Investigative	[8]
Purvalanol A	DMNQ7TM	Discovery agent	N.A.	Investigative	[9]
MERIOLIN 1	DMJT93H	Discovery agent	N.A.	Investigative	[7]
MERIOLIN 4	DMIJMZQ	Discovery agent	N.A.	Investigative	[7]
MERIOLIN 6	DMW5AXC	Discovery agent	N.A.	Investigative	[7]

Drug(s) Targeting Cyclin-dependent kinase 2 (CDK2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
R-roscovitine	DMSH108	Non-small-cell lung cancer	2C25.Y	Phase 2	[10]
Ro 31-7453	DM83QCL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[11]
PHA848125	DMS2Q9G	Thymic cancer	2C27	Phase 2	[12]
TG02	DMZFIGQ	Anaplastic astrocytoma	2A00.0	Phase 1/2	[13]
NUV-422	DMQJQNT	Malignant glioma	2A00.0	Phase 1/2	[14]
RGB-286638	DMEGOQP	Haematological malignancy	2B33.Y	Phase 1	[15]
FN-1501	DM7BMD6	Solid tumour/cancer	2A00-2F9Z	Phase 1	[16]
AG-024322	DMY4WVK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
PHA-793887	DM2Y4FG	Solid tumour/cancer	2A00-2F9Z	Phase 1	[17]
SNS-032	DMEITAS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[18]

Drug(s) Affected By Insulin (INS)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tolbutamide	DM02AWV	Advanced cancer	2A00-2F9Z	Approved	[19]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[20]
Epinephrine	DM3KJBC	Acute asthma	CA23	Approved	[21]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[22]
Fructose	DM43AN2	Vomiting	MD90	Approved	[23]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[24]
Glimepiride	DM5FSJA	Diabetic complication	5A2Y	Approved	[25]
Clonidine	DM6RZ9Q	Attention deficit hyperactivity disorder	6A05.Z	Approved	[26]
Propranolol	DM79NTF	Angina pectoris	BA40	Approved	[27]
Testosterone	DM7HUNW	Hot flushes	GA30	Approved	[28]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Cyclin A2 (CCNA2)	TTAMQ62	CCNA2_HUMAN	Inhibitor	[1]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[1]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
E3 ubiquitin-protein ligase XIAP	OT24GP9B	XIAP_HUMAN	Gene/Protein Processing	[2]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Protein Interaction/Cellular Processes	[3]

References

• [1] Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.
• [2] Downregulation of XIAP and induction of apoptosis by the synthetic cyclin-dependent kinase inhibitor GW8510 in non-small cell lung cancer cells. Cancer Biol Ther. 2006 Feb;5(2):165-70. doi: 10.4161/cbt.5.2.2316. Epub 2006 Feb 10.
• [3] GW8510 increases insulin expression in pancreatic alpha cells through activation of p53 transcriptional activity. PLoS One. 2012;7(1):e28808. doi: 10.1371/journal.pone.0028808. Epub 2012 Jan 5.
• [4] Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16.
• [5] 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
• [6] Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J Med Chem. 2003 Jan 16;46(2):222-36.
• [7] Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin com... J Med Chem. 2008 Feb 28;51(4):737-51.
• [8] Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases, Bioorg. Med. Chem. Lett. 20(13):3863-3867 (2010).
• [9] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [10] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [11] 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.
• [12] Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009 Aug 27;52(16):5152-63.
• [13] Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42.
• [14] ClinicalTrials.gov (NCT04541225) Phase 1/2 Dose Escalation, Safety, Pharmacokinetics, and Efficacy Study of NUV-422 in Adults With Recurrent or Refractory High-grade Gliomas and Solid Tumors. U.S.National Institutes of Health.
• [15] Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia. 2013 Dec;27(12):2366-75.
• [16] Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J Med Chem. 2018 Feb 22;61(4):1499-1518.
• [17] A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected h... Cell Cycle. 2011 Mar 15;10(6):963-70.
• [18] Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.
• [19] Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes. 1997 Mar;46(3):508-12. doi: 10.2337/diab.46.3.508.
• [20] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [21] A receptor mechanism for the inhibition of insulin release by epinephrine in man. J Clin Invest. 1967 Jan;46(1):86-94. doi: 10.1172/JCI105514.
• [22] Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Hypertension. 1999 Jul;34(1):83-8. doi: 10.1161/01.hyp.34.1.83.
• [23] Quinapril treatment restores the vasodilator action of insulin in fructose-hypertensive rats. Clin Exp Pharmacol Physiol. 2002 May-Jun;29(5-6):381-5. doi: 10.1046/j.1440-1681.2002.03668.x.
• [24] Retinoic acid can induce markers of endocrine transdifferentiation in pancreatic ductal adenocarcinoma: preliminary observations from an in vitro cell line model. J Clin Pathol. 2006 Jun;59(6):603-10. doi: 10.1136/jcp.2005.032003. Epub 2006 Feb 10.
• [25] Effects of prolonged in vitro exposure to sulphonylureas on the function and survival of human islets. J Diabetes Complications. 2005 Jan-Feb;19(1):60-4. doi: 10.1016/j.jdiacomp.2004.05.001.
• [26] Clonidine effect on insulin secretion and lipolysis in man. Acta Diabetol Lat. 1978 May-Aug;15(3-4):192-7. doi: 10.1007/BF02581064.
• [27] Beta-adrenergic contribution to glucagon-induced glucose production and insulin secretion in uremia. Am J Physiol. 1986 Sep;251(3 Pt 1):E322-7. doi: 10.1152/ajpendo.1986.251.3.E322.
• [28] Effect of testosterone replacement on whole body glucose utilisation and other cardiovascular risk factors in males with idiopathic hypogonadotrophic hypogonadism. Horm Metab Res. 1998 Oct;30(10):642-5. doi: 10.1055/s-2007-978950.