Details of Drug Off-Target (DOT)

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

• DOT Name: Kelch-like protein 31 (KLHL31)
• Synonyms: BTB and kelch domain-containing protein 6; Kelch repeat and BTB domain-containing protein 1; Kelch-like protein KLHL
• Gene Name: KLHL31
• Related Disease:
  Advanced cancer
  Carcinoma
  Congenital myopathy
  Neoplasm
• UniProt ID: KLH31_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MAPKKKIVKKNKGDINEMTIIVEDSPLNKLNALNGLLEGGNGLSCISSELTDASYGPNLL
  EGLSKMRQENFLCDLVIGTKTKSFDVHKSVMASCSEYFYNILKKDPSIQRVDLNDISPLG
  LATVIAYAYTGKLTLSLYTIGSIISAAVYLQIHTLVKMCSDFLIREMSVENCMYVVNIAE
  TYSLKNAKAAAQKFIRDNFLEFAESDQFMKLTFEQINELLIDDDLQLPSEIVAFQIAMKW
  LEFDQKRVKYAADLLSNIRFGTISAQDLVNYVQSVPRMMQDADCHRLLVDAMNYHLLPYH
  QNTLQSRRTRIRGGCRVLVTVGGRPGLTEKSLSRDILYRDPENGWSKLTEMPAKSFNQCV
  AVMDGFLYVAGGEDQNDARNQAKHAVSNFCRYDPRFNTWIHLASMNQKRTHFSLSVFNGL
  VYAAGGRNAEGSLASLECYVPSTNQWQPKTPLEVARCCHASAVADGRVLVTGGYIANAYS
  RSVCAYDPASDSWQELPNLSTPRGWHCAVTLSDRVYVMGGSQLGPRGERVDVLTVECYSP
  ATGQWSYAAPLQVGVSTAGVSALHGRAYLVGGWNEGEKKYKKCIQCFSPELNEWTEDDEL
  PEATVGVSCCTLSMPNNVTRESRASSVSSVPVSI
• Function: Transcriptional repressor in MAPK/JNK signaling pathway to regulate cellular functions. Overexpression inhibits the transcriptional activities of both the TPA-response element (TRE) and serum response element (SRE).
• Tissue Specificity: Strongly expressed in skeletal muscle and weakly in heart. According to PubMed:15302408, not expressed in other tissues. According to PubMed:18719355, abundantly expressed in both embryonic skeletal and heart tissues.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[1]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 31 (KLHL31).	[3]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Kelch-like protein 31 (KLHL31).	[4]
Tofacitinib	DMBS370	Approved	Tofacitinib increases the expression of Kelch-like protein 31 (KLHL31).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kelch-like protein 31 (KLHL31).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kelch-like protein 31 (KLHL31).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kelch-like protein 31 (KLHL31).	[8]

References

• [1] KLHL5 knockdown increases cellular sensitivity to anticancer drugs.Oncotarget. 2018 Dec 21;9(100):37429-37438. doi: 10.18632/oncotarget.26462. eCollection 2018 Dec 21.
• [2] Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice.J Clin Invest. 2017 Oct 2;127(10):3730-3740. doi: 10.1172/JCI93445. Epub 2017 Sep 5.
• [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] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [5] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.