Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7SBF5)

• DTT Name: Cellular tumor antigen p53 (TP53)
• Synonyms: Tumor suppressor p53; Phosphoprotein p53; P53; Antigen NY-CO-13
• Gene Name: TP53
• DTT Type: Clinical trial target; [1]
• UniProt ID: P53_HUMAN
• TTD ID: T15739
• Sequence:
  MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP
  DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAK
  SVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHE
  RCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNS
  SCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELP
  PGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPG
  GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD
• Function: Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2. Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Sphingolipid signaling pathway (hsa04071)
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Wnt signaling pathway (hsa04310)
  Neurotrophin signaling pathway (hsa04722)
  Thyroid hormone signaling pathway (hsa04919)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Huntington's disease (hsa05016)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Thyroid cancer (hsa05216)
  Basal cell carcinoma (hsa05217)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Activation of PUMA and translocation to mitochondria (R-HSA-139915)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)
  Oncogene Induced Senescence (R-HSA-2559585)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Stabilization of p53 (R-HSA-69541)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Activation of NOXA and translocation to mitochondria (R-HSA-111448)

Molecular Interaction Atlas (MIA) of This DTT

17 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Contusugene ladenovec	DMN9ETB	Oral cancer	2B6E	Phase 3	[1]
QPI-1002	DMDU5Y2	Renal transplantation	NE84	Phase 3	[2]
Thymoquinone	DMVDTR2	Polycystic ovarian syndrome	5A80.1	Phase 2/3	[3]
Ad-p53	DMJSWXL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
ALT-801	DM9KL7P	Acute myeloid leukaemia	2A60	Phase 2	[5]
APG-115	DMIFA0L	Prolymphocytic leukaemia	2A82.1	Phase 2	[6]
APR-246	DMNFADH	Ovarian cancer	2C73	Phase 2	[7]
INGN-225	DMF7J6D	Head and neck cancer	2D42	Phase 2	[8]
Kevetrin	DMFO6MH	Ovarian cancer	2C73	Phase 2	[6]
SGT-53	DMLYIPA	Pancreatic cancer	2C10	Phase 2	[9]
ISA-P53-01	DMQ5EYJ	Colorectal cancer	2B91.Z	Phase 1/2	[10]
CGM097	DMTCLM3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
COTI-2	DM6K3JQ	Cervical cancer	2C77.0	Phase 1	[6]
Dendritic cell vaccine	DMURVPF	Head and neck cancer	2D42	Phase 1	[11]
HDM201	DMVRTCW	Haematological malignancy	2B33.Y	Phase 1	[12]
ONYX-015	DMBVZND	Head and neck cancer	2D42	Phase 1	[13]
SAR-405838	DMC1AZP	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
INGN-234	DMJM38Q	Oral cancer	2B6E	Discontinued in Phase 2	[15]
Pifithrin-alpha	DM63OD7	Toxicity	N.A.	Terminated	[16]
TAR-1	DM197D0	Solid tumour/cancer	2A00-2F9Z	Terminated	[17]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine	DMC3PYM	Discovery agent	N.A.	Investigative	[18]
NU-8231	DMEUV5R	Discovery agent	N.A.	Investigative	[19]
NUTLIN-3	DM5KXFI	Discovery agent	N.A.	Investigative	[20]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Oral cancer	2C82	Oral tissue	7.01E-01	0.06	0.09
Acute myelocytic leukaemia	2C82	Bone marrow	7.90E-07	0.3	0.59
Rectal cancer	2C82	Rectal colon tissue	4.16E-01	0.2	0.87
Head and neck cancer	2C82	Head and neck tissue	1.22E-01	0.22	0.47

References

• [1] A review of contusugene ladenovec (Advexin) p53 therapy. Curr Opin Mol Ther. 2009 Feb;11(1):54-61.
• [2] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [3] Apoptosis as a mechanism for the treatment of adult T cell leukemia: promising drugs from benchside to bedside. Drug Discov Today. 2020 Jul;25(7):1189-1197.
• [4] Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. Cancer Gene Ther. 2003 Mar;10(3):224-38.
• [5] Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies. Clin Cancer Res. 2011 Dec 15;17(24):7765-75.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013 Oct 24;4:e881.
• [8] INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert Opin Biol Ther. 2010 Jun;10(6):983-91.
• [9] Transferrin receptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer to gemcitabine therapy. Cancer Gene Ther. 2013 Apr;20(4):222-8.
• [10] WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting.
• [11] Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother. 2004 Jul;53(7):633-41.
• [12] National Cancer Institute Drug Dictionary (drug id 761551).
• [13] Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell. 2004 Dec;6(6):611-23.
• [14] SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 2014 Oct 15;74(20):5855-65.
• [15] Prevent Oral Cancer With Mouthwash. Introgen Therapeutics.
• [16] An evaluation of the ability of pifithrin-alpha and -beta to inhibit p53 function in two wild-type p53 human tumor cell lines. Mol Cancer Ther. 2005 Sep;4(9):1369-77.
• [17] Regulation of host gene expression by HIV-1 TAR microRNAs. Retrovirology. 2013; 10: 86.
• [18] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [19] Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. J Med Chem. 2006 Oct 19;49(21):6209-21.
• [20] Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein intera... J Med Chem. 2009 Nov 26;52(22):7044-53.