Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX7NOSM)

• DOT Name: Kelch-like protein 18 (KLHL18)
• Gene Name: KLHL18
• UniProt ID: KLH18_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MVEDGAEELEDLVHFSVSELPSRGYGVMEEIRRQGKLCDVTLKIGDHKFSAHRIVLAASI
  PYFHAMFTNDMMECKQDEIVMQGMDPSALEALINFAYNGNLAIDQQNVQSLLMGASFLQL
  QSIKDACCTFLRERLHPKNCLGVRQFAETMMCAVLYDAANSFIHQHFVEVSMSEEFLALP
  LEDVLELVSRDELNVKSEEQVFEAALAWVRYDREQRGPYLPELLSNIRLPLCRPQFLSDR
  VQQDDLVRCCHKCRDLVDEAKDYHLMPERRPHLPAFRTRPRCCTSIAGLIYAVGGLNSAG
  DSLNVVEVFDPIANCWERCRPMTTARSRVGVAVVNGLLYAIGGYDGQLRLSTVEAYNPET
  DTWTRVGSMNSKRSAMGTVVLDGQIYVCGGYDGNSSLSSVETYSPETDKWTVVTSMSSNR
  SAAGVTVFEGRIYVSGGHDGLQIFSSVEHYNHHTATWHPAAGMLNKRCRHGAASLGSKMF
  VCGGYDGSGFLSIAEMYSSVADQWCLIVPMHTRRSRVSLVASCGRLYAVGGYDGQSNLSS
  VEMYDPETDCWTFMAPMACHEGGVGVGCIPLLTI
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL18) E3 ubiquitin ligase complex mediates the ubiquitination of AURKA leading to its activation at the centrosome which is required for initiating mitotic entry. Regulates light-and dark-dependent alpha-transducin localization changes in rod photoreceptors through UNC119 ubiquitination and degradation. Preferentially ubiquitinates the unphosphorylated form of UNC119 over the phosphorylated form. In the presence of UNC119, under dark-adapted conditions alpha-transducin mislocalizes from the outer segment to the inner part of rod photoreceptors which leads to decreased photoreceptor damage caused by light.

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 Kelch-like protein 18 (KLHL18).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Kelch-like protein 18 (KLHL18).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 18 (KLHL18).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kelch-like protein 18 (KLHL18).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Kelch-like protein 18 (KLHL18).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Kelch-like protein 18 (KLHL18).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kelch-like protein 18 (KLHL18).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Kelch-like protein 18 (KLHL18).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Kelch-like protein 18 (KLHL18).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kelch-like protein 18 (KLHL18).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Kelch-like protein 18 (KLHL18).	[10]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.