Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9RE37R)

• DOT Name: Kallikrein-2 (KLK2)
• Synonyms: EC 3.4.21.35; Glandular kallikrein-1; hGK-1; Tissue kallikrein-2
• Gene Name: KLK2
• UniProt ID: KLK2_HUMAN
• PDB ID: 4NFE; 4NFF
• EC Number: 3.4.21.35
• Pfam ID: PF00089
• Sequence:
  MWDLVLSIALSVGCTGAVPLIQSRIVGGWECEKHSQPWQVAVYSHGWAHCGGVLVHPQWV
  LTAAHCLKKNSQVWLGRHNLFEPEDTGQRVPVSHSFPHPLYNMSLLKHQSLRPDEDSSHD
  LMLLRLSEPAKITDVVKVLGLPTQEPALGTTCYASGWGSIEPEEFLRPRSLQCVSLHLLS
  NDMCARAYSEKVTEFMLCAGLWTGGKDTCGGDSGGPLVCNGVLQGITSWGPEPCALPEKP
  AVYTKVVHYRKWIKDTIAANP
• Function: Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 (R-HSA-5625886)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Kallikrein-2 (KLK2) affects the response to substance of Cisplatin.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kallikrein-2 (KLK2).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kallikrein-2 (KLK2).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kallikrein-2 (KLK2).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kallikrein-2 (KLK2).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kallikrein-2 (KLK2).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Kallikrein-2 (KLK2).	[6]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Kallikrein-2 (KLK2).	[7]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Kallikrein-2 (KLK2).	[8]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Kallikrein-2 (KLK2).	[9]
Dutasteride	DMQ4TJK	Approved	Dutasteride decreases the expression of Kallikrein-2 (KLK2).	[10]
Riluzole	DMECBWN	Approved	Riluzole decreases the expression of Kallikrein-2 (KLK2).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Kallikrein-2 (KLK2).	[12]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Kallikrein-2 (KLK2).	[13]
Cyproterone acetate	DMLMOIJ	Phase 4	Cyproterone acetate decreases the expression of Kallikrein-2 (KLK2).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Kallikrein-2 (KLK2).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Kallikrein-2 (KLK2).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Kallikrein-2 (KLK2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Kallikrein-2 (KLK2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Kallikrein-2 (KLK2).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Kallikrein-2 (KLK2).	[20]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Kallikrein-2 (KLK2).	[20]
EPZ-004777	DMLN4V5	Investigative	EPZ-004777 decreases the expression of Kallikrein-2 (KLK2).	[21]
[3H]mibolerone	DM6HDKQ	Investigative	[3H]mibolerone increases the expression of Kallikrein-2 (KLK2).	[22]

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 decreases the methylation of Kallikrein-2 (KLK2).	[18]

References

• [1] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis. 2001 Mar;22(3):409-14. doi: 10.1093/carcin/22.3.409.
• [4] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [5] Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation. Mol Cancer Ther. 2007 Jan;6(1):51-60. doi: 10.1158/1535-7163.MCT-06-0144. Epub 2007 Jan 11.
• [6] Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J Biol Chem. 2002 Dec 13;277(50):48366-71. doi: 10.1074/jbc.M209074200. Epub 2002 Oct 9.
• [7] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [8] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [9] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [10] Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs. 2007 Oct;25(5):491-7.
• [11] Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen-dependent and castration-resistant prostate cancer cells. Prostate. 2019 Feb;79(2):140-150. doi: 10.1002/pros.23719. Epub 2018 Oct 2.
• [12] Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. 2010 Aug;42(8):668-75. doi: 10.1038/ng.613. Epub 2010 Jul 4.
• [13] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [14] Dramatic suppression of plasma and urinary prostate specific antigen and human glandular kallikrein by antiandrogens in male-to-female transsexuals. J Urol. 2000 Mar;163(3):802-5.
• [15] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [16] Androgen responsive and refractory prostate cancer cells exhibit distinct curcumin regulated transcriptome. Cancer Biol Ther. 2008 Sep;7(9):1427-35. doi: 10.4161/cbt.7.9.6469. Epub 2008 Sep 4.
• [17] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [21] Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer. Nat Commun. 2020 Aug 19;11(1):4153. doi: 10.1038/s41467-020-18013-7.
• [22] Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.