Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYDT4A7)

• DOT Name: Hsp90 co-chaperone Cdc37 (CDC37)
• Synonyms: Hsp90 chaperone protein kinase-targeting subunit; p50Cdc37
• Gene Name: CDC37
• UniProt ID: CDC37_HUMAN
• PDB ID: 1US7; 2K5B; 2N5X; 2NCA; 2W0G; 5FWK; 5FWL; 5FWM; 5FWP; 5HPE; 7Z37; 7Z38; 7ZR0; 7ZR5; 7ZR6; 8GAE; 8GFT
• Pfam ID: PF08564 ; PF08565 ; PF03234
• Sequence:
  MVDYSVWDHIEVSDDEDETHPNIDTASLFRWRHQARVERMEQFQKEKEELDRGCRECKRK
  VAECQRKLKELEVAEGGKAELERLQAEAQQLRKEERSWEQKLEEMRKKEKSMPWNVDTLS
  KDGFSKSMVNTKPEKTEEDSEEVREQKHKTFVEKYEKQIKHFGMLRRWDDSQKYLSDNVH
  LVCEETANYLVIWCIDLEVEEKCALMEQVAHQTIVMQFILELAKSLKVDPRACFRQFFTK
  IKTADRQYMEGFNDELEAFKERVRGRAKLRIEKAMKEYEEEERKKRLGPGGLDPVEVYES
  LPEELQKCFDVKDVQMLQDAISKMDPTDAKYHMQRCIDSGLWVPNSKASEAKEGEEAGPG
  DPLLEAVPKTGDEKDVSV
• Function: Co-chaperone that binds to numerous kinases and promotes their interaction with the Hsp90 complex, resulting in stabilization and promotion of their activity. Inhibits HSP90AA1 ATPase activity.
• KEGG Pathway: PI3K-Akt sig.ling pathway (hsa04151)
• Reactome Pathway:
  Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382)
  Constitutive Signaling by EGFRvIII (R-HSA-5637810)
  Regulation of necroptotic cell death (R-HSA-5675482)
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  RHOBTB2 GTPase cycle (R-HSA-9013418)
  Constitutive Signaling by Overexpressed ERBB2 (R-HSA-9634285)
  Drug-mediated inhibition of ERBB2 signaling (R-HSA-9652282)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Resistance of ERBB2 KD mutants to trastuzumab (R-HSA-9665233)
  Resistance of ERBB2 KD mutants to sapitinib (R-HSA-9665244)
  Resistance of ERBB2 KD mutants to tesevatinib (R-HSA-9665245)
  Resistance of ERBB2 KD mutants to neratinib (R-HSA-9665246)
  Resistance of ERBB2 KD mutants to osimertinib (R-HSA-9665247)
  Resistance of ERBB2 KD mutants to afatinib (R-HSA-9665249)
  Resistance of ERBB2 KD mutants to AEE788 (R-HSA-9665250)
  Resistance of ERBB2 KD mutants to lapatinib (R-HSA-9665251)
  Signaling by ERBB2 ECD mutants (R-HSA-9665348)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Drug resistance in ERBB2 TMD/JMD mutants (R-HSA-9665737)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[8]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Hsp90 co-chaperone Cdc37 (CDC37).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Hsp90 co-chaperone Cdc37 (CDC37).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] 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.
• [4] 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.
• [5] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [6] 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.
• [7] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [8] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [9] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.