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

General Information of Drug (ID: DM65PTO)

• Drug Name: AMG 232 Drug Info
• Synonyms: KRT-232

Indication

Disease Entry	ICD 11	Status	REF
Merkel cell carcinoma	2C34	Phase 2	[1]
Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[2]

• Cross-matching ID:
  PubChem CID: 58573469
  CAS Number: CAS 1352066-68-2
  TTD Drug ID: DM65PTO

Molecule-Related Drug Atlas

Drug(s) Targeting Ubiquitin-protein ligase E3 Mdm2 (MDM2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RG7388	DMF5GZI	Acute myeloid leukaemia	2A60	Phase 3	[5]
APG-115	DMIFA0L	Prolymphocytic leukaemia	2A82.1	Phase 2	[6]
ALRN-6924	DMLBWT1	Haematological malignancy	2B33.Y	Phase 2	[6]
ASTX295	DM9EM5G	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[7]
HDM201	DMVRTCW	Haematological malignancy	2B33.Y	Phase 1	[6]
DS-3032	DMA2B5Y	Haematological malignancy	2B33.Y	Phase 1	[8]
RG7775	DMXBS6U	Acute myeloid leukaemia	2A60	Phase 1	[9]
JNJ-26854165	DMNSJ3C	Non-small-cell lung cancer	2C25.Y	Phase 1	[10]
BI 907828	DM2Z4YQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
MI-219	DM196LK	Triple negative breast cancer	2C60-2C65	Investigative	[12]

Drug(s) Affected By Nestin (NES)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cannabidiol	DM0659E	Dravet syndrome	8A61.11	Approved	[13]
Quercetin	DM3NC4M	Obesity	5B81	Approved	[14]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[15]
Arsenic trioxide	DM61TA4	Acute lymphoblastic leukaemia	2A85	Approved	[16]
Ciclosporin	DMAZJFX	Graft-versus-host disease	4B24	Approved	[17]
Testosterone enanthate	DMB6871	N. A.	N. A.	Approved	[18]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[19]
Ivermectin	DMDBX5F	Intestinal strongyloidiasis due to nematode parasite	1F6B	Approved	[20]
Clozapine	DMFC71L	Schizophrenia	6A20	Approved	[21]
Temozolomide	DMKECZD	Adenocarcinoma	2D40	Approved	[22]

Drug(s) Affected By Cellular tumor antigen p53 (TP53)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cisplatin	DMRHGI9	Adenocarcinoma	2D40	Approved	[23]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[24]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[25]
Arsenic trioxide	DM61TA4	Acute lymphoblastic leukaemia	2A85	Approved	[26]
Cidofovir	DMA13GD	Cytomegalovirus infection	1D82	Approved	[27]
Paclitaxel	DMLB81S	Breast carcinoma		Approved	[28]
Floxuridine	DM04LR2	Colorectal cancer	2B91.Z	Approved	[29]
Cannabidiol	DM0659E	Dravet syndrome	8A61.11	Approved	[30]
Mechlorethamine	DM0CVXA	Chronic myelogenous leukaemia	2A20.0	Approved	[31]
Fulvestrant	DM0YZC6	Breast cancer	2C60-2C65	Approved	[32]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Ubiquitin-protein ligase E3 Mdm2 (MDM2)	TT08GJW	MDM2_HUMAN	Modulator	[3]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Drug Response	[4]
Nestin (NES)	OTZ9PZ14	NEST_HUMAN	Gene/Protein Processing	[4]
Zinc finger E-box-binding homeobox 1	OTEDXTGD	ZEB1_HUMAN	Gene/Protein Processing	[4]

References

• [1] ClinicalTrials.gov (NCT03787602) This Study Evaluates KRT-232, a Novel Oral Small Molecule Inhibitor of MDM2, for the Treatment of Patients With (p53WT) Merkel Cell Carcinoma Who Have Failed Anti-PD-1/ PD-L1 Immunotherapy. U.S. National Institutes of Health.
• [2] ClinicalTrials.gov (NCT02110355) A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma. U.S. National Institutes of Health.
• [3] Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332-41.
• [4] Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells. Cell Death Dis. 2018 Jul 18;9(8):792. doi: 10.1038/s41419-018-0825-1.
• [5] Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015 Apr 30;6(12):10207-21.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of Astex Pharmaceuticals.
• [8] Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217-36.
• [9] Phase I clinical trail of RG7775 for treating Acute myelogenous leukemia. Roche.
• [10] Serdemetan antagonizes the Mdm2-HIF1alpha axis leading to decreased levels of glycolytic enzymes. PLoS One. 2013 Sep 6;8(9):e74741.
• [11] MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874.
• [12] MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene. 2011 Jan 6;30(1):117-26.
• [13] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [14] Quercetin in elimination of tumor initiating stem-like and mesenchymal transformation property in head and neck cancer. Head Neck. 2013 Mar;35(3):413-9. doi: 10.1002/hed.22982. Epub 2012 Mar 16.
• [15] Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023 Mar 15;487:153461. doi: 10.1016/j.tox.2023.153461. Epub 2023 Feb 16.
• [16] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] p53-R175H mutant gains new function in regulation of doxorubicin-induced apoptosis. Int J Cancer. 2005 Apr 10;114(3):331-6. doi: 10.1002/ijc.20818.
• [24] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [25] Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line. Toxicol Appl Pharmacol. 2006 Oct 1;216(1):89-97. doi: 10.1016/j.taap.2006.04.015. Epub 2006 May 19.
• [26] Quantitative analysis of gene expression changes in response to genotoxic compounds. Toxicol In Vitro. 2017 Mar;39:15-28. doi: 10.1016/j.tiv.2016.11.004. Epub 2016 Nov 5.
• [27] Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells. Oncol Res. 2000;12(9-10):397-408. doi: 10.3727/096504001108747855.
• [28] Gallic acid potentiates the apoptotic effect of paclitaxel and carboplatin via overexpression of Bax and P53 on the MCF-7 human breast cancer cell line. J Biochem Mol Toxicol. 2021 Feb;35(2):e22638. doi: 10.1002/jbt.22638. Epub 2020 Oct 1.
• [29] Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage. Nucleic Acids Res. 2009 Jan;37(1):78-95. doi: 10.1093/nar/gkn910. Epub 2008 Nov 16.
• [30] Role of miRNA in the regulation of cannabidiol-mediated apoptosis in neuroblastoma cells. Oncotarget. 2019 Jan 1;10(1):45-59. doi: 10.18632/oncotarget.26534. eCollection 2019 Jan 1.
• [31] Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes. Chem Res Toxicol. 2022 Apr 18;35(4):636-650. doi: 10.1021/acs.chemrestox.1c00420. Epub 2022 Mar 21.
• [32] Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex. Br J Cancer. 2013 Nov 12;109(10):2751-62. doi: 10.1038/bjc.2013.583. Epub 2013 Oct 29.