Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: DNA topoisomerase I (TOP1)
• Synonyms: DNA topoisomerase I
• Gene Name: TOP1
• DTT Type: Successful target; [1]
• Related Disease:
  Bacterial infection [ICD-11: 1A00-1C4Z]
  Colorectal cancer [ICD-11: 2B91]
  Lung cancer [ICD-11: 2C25]
  Ovarian cancer [ICD-11: 2C73]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• BioChemical Class: Topoisomerase
• UniProt ID: TOP1_HUMAN
• TTD ID: T09826
• EC Number: EC 5.6.2.2
• Sequence:
  MSGDHLHNDSQIEADFRLNDSHKHKDKHKDREHRHKEHKKEKDREKSKHSNSEHKDSEKK
  HKEKEKTKHKDGSSEKHKDKHKDRDKEKRKEEKVRASGDAKIKKEKENGFSSPPQIKDEP
  EDDGYFVPPKEDIKPLKRPRDEDDADYKPKKIKTEDTKKEKKRKLEEEEDGKLKKPKNKD
  KDKKVPEPDNKKKKPKKEEEQKWKWWEEERYPEGIKWKFLEHKGPVFAPPYEPLPENVKF
  YYDGKVMKLSPKAEEVATFFAKMLDHEYTTKEIFRKNFFKDWRKEMTNEEKNIITNLSKC
  DFTQMSQYFKAQTEARKQMSKEEKLKIKEENEKLLKEYGFCIMDNHKERIANFKIEPPGL
  FRGRGNHPKMGMLKRRIMPEDIIINCSKDAKVPSPPPGHKWKEVRHDNKVTWLVSWTENI
  QGSIKYIMLNPSSRIKGEKDWQKYETARRLKKCVDKIRNQYREDWKSKEMKVRQRAVALY
  FIDKLALRAGNEKEEGETADTVGCCSLRVEHINLHPELDGQEYVVEFDFLGKDSIRYYNK
  VPVEKRVFKNLQLFMENKQPEDDLFDRLNTGILNKHLQDLMEGLTAKVFRTYNASITLQQ
  QLKELTAPDENIPAKILSYNRANRAVAILCNHQRAPPKTFEKSMMNLQTKIDAKKEQLAD
  ARRDLKSAKADAKVMKDAKTKKVVESKKKAVQRLEEQLMKLEVQATDREENKQIALGTSK
  LNYLDPRITVAWCKKWGVPIEKIYNKTQREKFAWAIDMADEDYEF
• Function: Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component ARNTL/BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the ARNTL/BMAL1 promoter. Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex.
• Reactome Pathway: SUMOylation of DNA replication proteins (R-HSA-4615885)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
B-Lactams	DMR8YD6	Bacterial infection	1A00-1C4Z	Approved	[2]
Belotecan hydrocholoride	DM3SRJZ	Small-cell lung cancer	2C25.Y	Approved	[3], [4]
Irinotecan	DMP6SC2	Colorectal cancer	2B91.Z	Approved	[5]
Topetecan	DMAE6LK	Small-cell lung cancer	2C25.Y	Approved	[1]
Topotecan	DMP6G8T	Ovarian cancer	2C73	Approved	[5]

41 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Camptothecin	DM6CHNJ	Solid tumour/cancer	2A00-2F9Z	Phase 3	[6], [7]
Edotecarin	DM3ZL7D	Gastric adenocarcinoma	2B72	Phase 3	[8]
Etirinotecan pegol	DMQHX1Y	Breast cancer	2C60-2C65	Phase 3	[9]
Exatecan	DMCA7FN	Solid tumour/cancer	2A00-2F9Z	Phase 3	[10]
Karenitecin	DMCRGY4	Lung cancer	2C25.0	Phase 3	[11]
Rubitecan	DMDWU1S	Human immunodeficiency virus infection	1C62	Phase 3	[12], [13]
9-AMINOCAMPTOTHECIN	DMQXYRG	Acquired immune deficiency syndrome	1C62.3	Phase 2	[14]
AR-67	DM8A71F	Glioblastoma multiforme	2A00.0	Phase 2	[15]
Beta-lapachone	DMMI84K	Solid tumour/cancer	2A00-2F9Z	Phase 2	[16]
CKD602	DMW9F1G	Solid tumour/cancer	2A00-2F9Z	Phase 2	[17]
CRLX101	DMQUWXY	Non-small-cell lung cancer	2C25.Y	Phase 2	[18]
Diflomotecan	DM20ATW	Solid tumour/cancer	2A00-2F9Z	Phase 2	[19]
EQ-917	DMD4YRG	Solid tumour/cancer	2A00-2F9Z	Phase 2	[20]
Gimatecan	DMSKMET	Breast cancer	2C60-2C65	Phase 2	[21]
LE-SN38	DMW50NF	Colorectal cancer	2B91.Z	Phase 2	[22], [23]
PEG-SN38	DMX9ZM4	Breast cancer	2C60-2C65	Phase 2	[24]
Pegamotecan	DMFL96Z	Esophageal cancer	2B70	Phase 2	[25]
Polyglutamate camptothecin	DMXROM7	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
TLC-388	DMGWP8L	Solid tumour/cancer	2A00-2F9Z	Phase 2	[26]
XR-5000	DMOKUA5	Colorectal cancer	2B91.Z	Phase 2	[27]
DS-7300	DMK4VY9	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[28]
PEN-866	DMLPTOF	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[29]
ABI-011	DM1KD7U	Lymphoma	2A80-2A86	Phase 1	[30]
Afeletecan	DMNF3GW	Breast cancer	2C60-2C65	Phase 1	[31]
CZ-48	DMAY6X2	Lymphoma	2A80-2A86	Phase 1	[32]
Daniquidone	DMWT5RS	Lymphoma	2A80-2A86	Phase 1	[33]
DFP 13318	DMI8QNB	Solid tumour/cancer	2A00-2F9Z	Phase 1	[29]
DRF-1042	DMJY9TW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[34], [14]
DS-6157	DMTKZ1Q	Gastrointestinal stromal tumour	2B5B	Phase 1	[35]
ELOMOTECAN HYDROCHLORIDE	DMQPI4V	Solid tumour/cancer	2A00-2F9Z	Phase 1	[36], [37]
Genz-644282	DMIXABW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[38]
GZ402674	DMTWNLY	Solid tumour/cancer	2A00-2F9Z	Phase 1	[39]
INTOPLICINE	DMXPLMN	Solid tumour/cancer	2A00-2F9Z	Phase 1	[40]
IT-141	DMAYD7O	Solid tumour/cancer	2A00-2F9Z	Phase 1	[29]
LMP400	DM4FW2E	Lymphoma	2A80-2A86	Phase 1	[41]
LMP744	DMUCQYW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[41]
MLN-576	DMCVO2Y	Acute lymphoblastic leukaemia	2A85	Phase 1	[42], [43]
Namitecan	DMMKZYV	Solid tumour/cancer	2A00-2F9Z	Phase 1	[44]
Tafluposide	DMV8IQW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[45]
XMT-1001	DM4MDCH	Solid tumour/cancer	2A00-2F9Z	Phase 1	[46]
(S)-DRF-1042	DMX1ZQV	Bladder cancer	2C94	Clinical trial	[39]

13 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Becatecarin	DMRQV8I	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 3	[47]
Atiratecan	DMZEMG6	Colorectal cancer	2B91.Z	Discontinued in Phase 2	[48]
Lurtotecan	DMF1RTW	Ovarian cancer	2C73	Discontinued in Phase 2	[49], [39]
NK-611	DM5OVGH	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[50]
S-16020-2	DM51WJN	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[51]
DE-310	DMAOZH3	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[52]
BE-13793C	DM6WQ8F	Solid tumour/cancer	2A00-2F9Z	Terminated	[53]
BN-80245	DMMZ9DY	Solid tumour/cancer	2A00-2F9Z	Terminated	[54]
CZ-112	DMF8TCI	Solid tumour/cancer	2A00-2F9Z	Terminated	[32]
Datelliptium chloride	DMR80AL	Breast cancer	2C60-2C65	Terminated	[55]
ED-110	DMJN7MY	Solid tumour/cancer	2A00-2F9Z	Terminated	[56], [57]
PIROXANTRONE	DMR87MO	Solid tumour/cancer	2A00-2F9Z	Terminated	[58]
TAN-1496	DMU3BDY	Solid tumour/cancer	2A00-2F9Z	Terminated	[59]

33 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5Z,9Z)-5,9-heptacosadienoic acid	DMA97CS	Discovery agent	N.A.	Investigative	[60]
10-hydroxycamptothecin	DM9WLN4	Discovery agent	N.A.	Investigative	[61]
2,3-Dimethoxybenzo[i]phenanthridines	DMEB47J	Discovery agent	N.A.	Investigative	[62]
3,3'-(4-phenylpyridine-2,6-diyl)diphenol	DMJVKMO	Discovery agent	N.A.	Investigative	[63]
3-(4-phenyl-2,4'-bipyridin-6-yl)phenol	DMSZ1VC	Discovery agent	N.A.	Investigative	[63]
3-(4-phenyl-6-(thiophen-2-yl)pyridin-2-yl)-phenol	DM0OF64	Discovery agent	N.A.	Investigative	[63]
3-(4-phenyl-6-(thiophen-3-yl)pyridin-2-yl)-phenol	DMTR8SZ	Discovery agent	N.A.	Investigative	[63]
3-(6-phenyl-2,4'-bipyridin-4-yl)phenol	DM8ZUBY	Discovery agent	N.A.	Investigative	[63]
4-(4,6-diphenylpyridin-2-yl)phenol	DMETK18	Discovery agent	N.A.	Investigative	[63]
4-(6-phenyl-2,4'-bipyridin-4-yl)phenol	DMJ81IL	Discovery agent	N.A.	Investigative	[63]
4-hydroxysaprothoquinone	DMPIV6J	Discovery agent	N.A.	Investigative	[64]
5-hydroxy-1H-indole-3-acetic acid	DM98OEQ	Discovery agent	N.A.	Investigative	[65]
7-amino-4-hydroxy-2-naphthalenesulfonic acid	DMDUB63	Discovery agent	N.A.	Investigative	[65]
A35566-A	DMFNR3Y	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
ATI-1150	DMN5VDB	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
CHO793076	DMZHO3S	Discovery agent	N.A.	Investigative	[66]
CRISNATOL MESILATE	DMY0GXM	Discovery agent	N.A.	Investigative	[67]
Dibenzo-p-dioxin-2-carboxylic acid	DMOKNXE	Discovery agent	N.A.	Investigative	[65]
DTS-108	DM7PNOK	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
E-758	DMY6DM5	Solid tumour/cancer	2A00-2F9Z	Investigative	[68]
Homocamptothecins (hCPTs)	DMCIRY0	Discovery agent	N.A.	Investigative	[69]
IDN-5174	DMNS9KW	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
IDN-6384	DM6TEWZ	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
KT6006	DMXIUO5	Discovery agent	N.A.	Investigative	[70]
KT6528	DMRDZ7I	Discovery agent	N.A.	Investigative	[70]
MEN-14295	DMEIRDX	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
Nogalamycin	DM50TCG	Discovery agent	N.A.	Investigative	[71]
NSC-341622	DMVGLH7	Discovery agent	N.A.	Investigative	[72]
Quinizarin	DMRQCK3	Discovery agent	N.A.	Investigative	[65]
ROSETTACIN	DMN802V	Discovery agent	N.A.	Investigative	[72]
SER-203	DMIKT7W	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
TH-1320	DMLC8PX	Solid tumour/cancer	2A00-2F9Z	Investigative	[39]
TOPOSTATIN	DMNZQO9	Discovery agent	N.A.	Investigative	[73]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	6.65E-01	0.2	0.39
Rectal cancer	2C82	Rectal colon tissue	1.35E-02	0.37	1.49
Ovarian cancer	2C82	Ovarian tissue	2.65E-01	0.44	0.64
Breast cancer	2C82	Breast tissue	1.05E-01	0.17	0.27
Myelodysplastic syndrome	2C82	Bone marrow	1.09E-01	0.15	0.27
Gastric cancer	2C82	Gastric tissue	1.81E-01	0.79	0.95
Bladder cancer	2C82	Bladder tissue	5.84E-07	0.97	4.96

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