Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBK7278)

• DOT Name: Protein HEXIM1 (HEXIM1)
• Synonyms: Cardiac lineage protein 1; Estrogen down-regulated gene 1 protein; Hexamethylene bis-acetamide-inducible protein 1; Menage a quatre protein 1
• Gene Name: HEXIM1
• UniProt ID: HEXI1_HUMAN
• PDB ID: 2GD7; 3S9G
• Pfam ID: PF15313
• Sequence:
  MAEPFLSEYQHQPQTSNCTGAAAVQEELNPERPPGAEERVPEEDSRWQSRAFPQLGGRPG
  PEGEGSLESQPPPLQTQACPESSCLREGEKGQNGDDSSAGGDFPPPAEVEPTPEAELLAQ
  PCHDSEASKLGAPAAGGEEEWGQQQRQLGKKKHRRRPSKKKRHWKPYYKLTWEEKKKFDE
  KQSLRASRIRAEMFAKGQPVAPYNTTQFLMDDHDQEEPDLKTGLYSKRAAAKSDDTSDDD
  FMEEGGEEDGGSDGMGGDGSEFLQRDFSETYERYHTESLQNMSKQELIKEYLELEKCLSR
  MEDENNRLRLESKRLGGDDARVRELELELDRLRAENLQLLTENELHRQQERAPLSKFGD
• Function: Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor. Core component of the 7SK RNP complex: in cooperation with 7SK snRNA sequesters P-TEFb in a large inactive 7SK snRNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation. May also regulate NF-kappa-B, ESR1, NR3C1 and CIITA-dependent transcriptional activity. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway.
• Tissue Specificity: Ubiquitously expressed with higher expression in placenta. HEXIM1 and HEXIM2 are differentially expressed. Expressed in endocrine tissues.

Molecular Interaction Atlas (MIA) of This DOT

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein HEXIM1 (HEXIM1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein HEXIM1 (HEXIM1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein HEXIM1 (HEXIM1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein HEXIM1 (HEXIM1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein HEXIM1 (HEXIM1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein HEXIM1 (HEXIM1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein HEXIM1 (HEXIM1).	[7]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Protein HEXIM1 (HEXIM1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein HEXIM1 (HEXIM1).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein HEXIM1 (HEXIM1).	[10]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Protein HEXIM1 (HEXIM1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein HEXIM1 (HEXIM1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein HEXIM1 (HEXIM1).	[14]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Protein HEXIM1 (HEXIM1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein HEXIM1 (HEXIM1).	[16]
I-BET151	DMYRUH2	Investigative	I-BET151 increases the expression of Protein HEXIM1 (HEXIM1).	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein HEXIM1 (HEXIM1).	[12]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [7] 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.
• [8] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016 Nov 1;139(9):2047-55. doi: 10.1002/ijc.30256. Epub 2016 Jul 30.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10;6(19):17698-712. doi: 10.18632/oncotarget.4131.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019 Jan 15;9(2):4. doi: 10.1038/s41408-018-0165-5.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.