Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT30C9G)

• DTT Name: C-X-C chemokine receptor type 2 (CXCR2)
• Synonyms: Interleukin-8 receptor B; IL8RB; IL-8R B; IL-8 receptor type 2; High affinity interleukin-8 receptor B; GRO/MGSA receptor; CXCR-2; CXC-R2; CDw128b; CD182
• Gene Name: CXCR2
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: CXCR2_HUMAN
• TTD ID: T56923
• Sequence:
  MEDFNMESDSFEDFWKGEDLSNYSYSSTLPPFLLDAAPCEPESLEINKYFVVIIYALVFL
  LSLLGNSLVMLVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCK
  VVSLLKEVNFYSGILLLACISVDRYLAIVHATRTLTQKRYLVKFICLSIWGLSLLLALPV
  LLFRRTVYSSNVSPACYEDMGNNTANWRMLLRILPQSFGFIVPLLIMLFCYGFTLRTLFK
  AHMGQKHRAMRVIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQETCERRNHIDRALDATE
  ILGILHSCLNPLIYAFIGQKFRHGLLKILAIHGLISKDSLPKDSRPSFVGSSSGHTSTTL
• Function: Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Binds to IL-8 with high affinity. Also binds with high affinity to CXCL3, GRO/MGSA and NAP-2. Receptor for interleukin-8 which is a powerful neutrophil chemotactic factor.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Chemokine signaling pathway (hsa04062)
  Endocytosis (hsa04144)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Clotrimazole	DMMFCIH	Cutaneous candidiasis	1F23.14	Approved	[2]
Ibuprofen	DM8VCBE	Dysmenorrhea	GA34.3	Approved	[1]

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Reparixin	DMVBA7I	Pancreatic islet transplantation failure	NE84	Phase 3	[1]
AZD-5069	DM3JSFK	Asthma	CA23	Phase 2	[3]
GSK1325756	DMA6RBF	Chronic obstructive pulmonary disease	CA22	Phase 2	[4]
PS-938285	DMHZIFJ	Chronic obstructive pulmonary disease	CA22	Phase 2	[5]
RIST4721	DMA3DKO	Hidradenitis suppurativa	ED92.0	Phase 2	[6]
SB-265610	DM8TKG5	Asthma	CA23	Phase 2	[7]
SB-656933	DMCY785	Chronic obstructive pulmonary disease	CA22	Phase 2	[8]
SCH-527123	DMPUAOE	Chronic obstructive pulmonary disease	CA22	Phase 2	[9]
AZD-5122	DMQEO4V	Chronic obstructive pulmonary disease	CA22	Phase 1	[10]
AZD4721	DM36EY7	Chronic obstructive pulmonary disease	CA22	Phase 1	[11]
SX-682	DMHMG6X	Melanoma	2C30	Phase 1	[12]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
INDOPROFEN	DM5QSKN	Gout	FA25	Withdrawn from market	[1]
R-ketoprofen	DMHSUQ1	N. A.	N. A.	Discontinued in Phase 2	[1]
SB-332235	DM57HZW	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 1	[7]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-157695	DMDSR1X	Schizophrenia	6A20	Preclinical	[13]

21 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(R)-2-(4-Isobutyl-phenyl)-N-methoxy-propionamide	DMR8E0G	Discovery agent	N.A.	Investigative	[1]
(R)-2-(4-Isobutyl-phenyl)-propionamide	DMBQ0PR	Discovery agent	N.A.	Investigative	[1]
(R)-3-(4-Isobutyl-phenyl)-butan-2-one	DMQ2KF8	Discovery agent	N.A.	Investigative	[1]
(R)-N-Hydroxy-2-(4-isobutyl-phenyl)-propionamide	DMWRIQG	Discovery agent	N.A.	Investigative	[1]
1-(2-bromophenyl)-3-(4-cyano-2-hydroxyphenyl)urea	DMU9T3A	Discovery agent	N.A.	Investigative	[14]
1-(2-Hydroxy-3-nitro-phenyl)-3-phenyl-urea	DM3WXET	Discovery agent	N.A.	Investigative	[15]
1-(2-hydroxy-4-nitrophenyl)-3-phenylurea	DMN4G7U	Discovery agent	N.A.	Investigative	[16]
1-(2-Hydroxy-5-nitro-phenyl)-3-phenyl-urea	DMPLHEY	Discovery agent	N.A.	Investigative	[15]
1-(3-cyano-2-hydroxyphenyl)-3-phenylurea	DM9KTH6	Discovery agent	N.A.	Investigative	[14]
1-(4-cyano-2-hydroxyphenyl)-3-phenylurea	DMIU3C8	Discovery agent	N.A.	Investigative	[14]
1-(5-chloro-2-hydroxy-4-nitrophenyl)-3-phenylurea	DMDTYAF	Discovery agent	N.A.	Investigative	[14]
2-(3-Isobutyl-phenyl)-propionic acid	DM59VBG	Discovery agent	N.A.	Investigative	[1]
2-(3-Isopropyl-phenyl)-propionic acid	DMUOWNE	Discovery agent	N.A.	Investigative	[1]
2-[3-(1-Hydroxy-propyl)-phenyl]-propionic acid	DMDT9KG	Discovery agent	N.A.	Investigative	[1]
2-[3-(1-Phenyl-ethyl)-phenyl]-propionic acid	DMWIUR0	Discovery agent	N.A.	Investigative	[1]
2-[3-(2-Methyl-butyl)-phenyl]-propionic acid	DMKSDT4	Discovery agent	N.A.	Investigative	[1]
5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-ol	DMG2VQB	Discovery agent	N.A.	Investigative	[17]
CXCL8	DMG1SXD	Psoriasis vulgaris	EA90	Investigative	[18]
Il-8((3-73))K11R	DM10Z5W	Discovery agent	N.A.	Investigative	[19]
SB 272844	DMVO8P5	Discovery agent	N.A.	Investigative	[20]
SX-517	DMZGX48	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	8.82E-01	-0.23	-0.21
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	1.34E-01	0.21	0.19

References

• [1] 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors. J Med Chem. 2005 Jun 30;48(13):4312-31.
• [2] Mode of action of clotrimazole: implications for therapy. Am J Obstet Gynecol. 1985 Aug 1;152(7 Pt 2):939-44.
• [3] Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. J Pharmacol Exp Ther. 2015 May;353(2):340-50.
• [4] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [5] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
• [6] A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis. Dermatol Ther (Heidelb). 2021 Dec;11(6):2179-2193.
• [7] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [8] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [9] CXCR2 Antagonist MK-7123.A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease.Am J Respir Crit Care Med.2015 May 1;191(9):1001-11.
• [10] Molecular Approaches To Target GPCRs in Cancer Therapy. Pharmaceuticals 2011, 4(4), 567-589.
• [11] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800038326)
• [12] Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models. Clin Cancer Res. 2020 Mar 15;26(6):1420-1431.
• [13] Interleukin-8 receptor antagonists in pulmonary diseases. Curr Opin Pharmacol. 2001 Jun;1(3):242-7.
• [14] Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1713-7.
• [15] Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor. J Med Chem. 2004 Mar 11;47(6):1319-21.
• [16] Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J Biol Chem. 1998 Apr 24;273(17):10095-8.
• [17] Hit-to-Lead studies: the discovery of potent, orally bioavailable thiazolopyrimidine CXCR2 receptor antagonists. Bioorg Med Chem Lett. 2006 Feb 15;16(4):960-3.
• [18] Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11791-6.
• [19] Il-8((3-73))K11R is a high affinity agonist of the neutrophil CXCR1 and CXCR2. Biochem Biophys Res Commun. 2001 Aug 24;286(3):595-600.
• [20] The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogene-alpha-mediated inhibition of spontaneous neutrophil apoptosis. Pulm Pharmacol Ther. 2002;15(2):103-10.
• [21] Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2. J Med Chem. 2014 Oct 23;57(20):8378-97.