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

General Information of Drug (ID: DMGYBZI)

• Drug Name: PHA-739358 Drug Info
• Synonyms: Danusertib; PHA 739358; Danusertib, PHA-739358; (R)-N-(5-(2-methoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide; 5-Amido-pyrrolopyrazole 9d

Indication

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Phase 2	[1]

• Cross-matching ID:
  PubChem CID: 11442891
  ChEBI ID: CHEBI:94490
  CAS Number: CAS 827318-97-8
  TTD Drug ID: DMGYBZI

Molecule-Related Drug Atlas

Drug(s) Targeting Aurora kinase B (AURKB)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AT9283	DMQ94CT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[5]
VX-680	DM93YKJ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[7]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
CYC116	DMUMHXT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
AMG 900	DMASGXJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
SNS-314	DMAC5F2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
BI-847325	DMY4B6J	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
R763	DME0CJ9	Haematological malignancy	2B33.Y	Phase 1	[13]
GSK1070916	DMXRPT6	Advanced solid tumour	2A00-2F9Z	Phase 1	[14]

Drug(s) Targeting Aurora B messenger RNA (AURKB mRNA)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[15]
SU 6656	DMF1P6W	Discovery agent	N.A.	Investigative	[16]
6-bromoindirubin-3-oxime	DM12WYV	Discovery agent	N.A.	Investigative	[15]
7-fluoroindirubin-3-oxime	DMQD34N	Discovery agent	N.A.	Investigative	[15]
PMID21742770C1	DME3JMH	Discovery agent	N.A.	Investigative	[17]
Indirubin-3-acetoxime	DM3UR1E	Discovery agent	N.A.	Investigative	[15]
CGP-57380	DMFPOUC	Discovery agent	N.A.	Investigative	[16]
PMID20855207C25	DMNEB6J	Discovery agent	N.A.	Investigative	[18]
Indirubin-3-methoxime	DMZ5ODC	Discovery agent	N.A.	Investigative	[15]
4-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine	DM9MPHF	Discovery agent	N.A.	Investigative	[19]

Drug(s) Targeting Aurora kinase A (AURKA)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AT9283	DMQ94CT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[5]
MLN8237	DMO8PT9	Solid tumour/cancer	2A00-2F9Z	Phase 3	[20]
VX-680	DM93YKJ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[7]
ENMD-2076	DMJZVPB	Acute myeloid leukaemia	2A60	Phase 2	[3]
LY3295668	DM8RJTB	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[21]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
MLN8054	DMUANF3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
CYC116	DMUMHXT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
AMG 900	DMASGXJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]

Drug(s) Targeting Aurora kinase C (AURKC)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[7]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
AMG 900	DMASGXJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
SNS-314	DMAC5F2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
GSK1070916	DMXRPT6	Advanced solid tumour	2A00-2F9Z	Phase 1	[14]
GSK1070916A	DMCJUI9	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
MK-6592	DMB5NOI	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[22]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[15]
SU 6656	DMF1P6W	Discovery agent	N.A.	Investigative	[16]
6-bromoindirubin-3-oxime	DM12WYV	Discovery agent	N.A.	Investigative	[15]

Drug(s) Affected By Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Testosterone	DM7HUNW	Hot flushes	GA30	Approved	[23]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[23]
Gefitinib	DM15F0X	Colon adenocarcinoma		Approved	[24]
Sunitinib	DMCBJSR	Acute undifferentiated leukemia		Approved	[25]
Rosuvastatin	DMMIQ7G	Arteriosclerosis	BD40	Approved	[26]
Ciprofloxacin XR	DM2NLS9	Acute gonococcal cervicitis		Approved	[27]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[28]
Quercetin	DM3NC4M	Obesity	5B81	Approved	[29]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[30]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[31]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Aurora B messenger RNA (AURKB mRNA)	TT9RTBL	AURKB_HUMAN	Inhibitor	[2]
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[3]
Aurora kinase B (AURKB)	TT5LS6T	AURKB_HUMAN	Inhibitor	[3]
Aurora kinase C (AURKC)	TTLYXIT	AURKC_HUMAN	Inhibitor	[2]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Drug Response	[4]

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: 7937).
• [2] Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. J Med Chem. 2005 Apr 21;48(8):3080-4.
• [3] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [4] Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. PLoS One. 2011 Apr 26;6(4):e19164. doi: 10.1371/journal.pone.0019164.
• [5] A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study. Clin Cancer Res. 2015 Jan 15;21(2):267-73.
• [6] 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.
• [7] Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. J Pharmacol Exp Ther. 2012 Dec;343(3):617-27.
• [8] 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: 1936).
• [9] Clinical pipeline report, company report or official report of Cyclacel.
• [10] Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010 Dec 1;70(23):9846-54.
• [11] SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2010 Mar;65(4):707-17.
• [12] doi: 10.1158/1535-7163.TARG-13-B281
• [13] Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2010 Jan;136(1):99-113.
• [14] Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J Med Chem. 2010 May 27;53(10):3973-4001.
• [15] An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted in... J Med Chem. 2007 Aug 23;50(17):4027-37.
• [16] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [17] A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells. ACS Med Chem Lett. 2012 Dec 13;3(12):1034-1038.
• [18] Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6739-43.
• [19] Discovery of a new series of Aurora inhibitors through truncation of GSK1070916. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2552-5.
• [20] Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models. Journal of Clinical Oncology, 2009:8553.
• [21] Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy. Mol Cancer Ther. 2019 Dec;18(12):2207-2219.
• [22] Clinical experience with aurora kinase inhibitors: a review. Oncologist. 2009 Aug;14(8):780-93.
• [23] Localization of breast cancer resistance protein (Bcrp) in endocrine organs and inhibition of its transport activity by steroid hormones. Cell Tissue Res. 2012 Aug;349(2):551-63. doi: 10.1007/s00441-012-1417-5. Epub 2012 May 13.
• [24] Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst. 2006 Dec 6;98(23):1739-42.
• [25] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [26] ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010 May;87(5):558-62.
• [27] Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism. Chem Biol Interact. 2016 Apr 25;250:1-11.
• [28] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [29] Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem. 2008 Aug;106(4):1855-65. doi: 10.1111/j.1471-4159.2008.05537.x. Epub 2008 Jul 4.
• [30] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [31] Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther. 2005 Jul;4(7):747-52.