Novel CMKLR1 Inhibitors for Application in Demyelinating Disease.

Novel CMKLR1 Inhibitors for Application in Demyelinating Disease.

Publication date: May 09, 2019

Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo. Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy. α-NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated α-NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo. These findings suggest that α-NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.

Open Access PDF

, Kumar, LaJevic, M., Pandrala, M., Jacobo, S.A., Malhotra, S.V., and Zabel, B.A. Novel CMKLR1 Inhibitors for Application in Demyelinating Disease. 17973. 2019 Sci Rep (9):1.

Concepts Keywords
Antagonist Branches of biology
Autoimmune Disorders Experimental autoimmune encephalomyelitis
Chemokine Chemerin
Demyelinating Diseases CMKLR1
FDA MS
Histological Demyelinating diseases
Iodide
Methoxy
Multiple Sclerosis
Ortho
Receptor
Sci
Small Molecule
Toxicity

Semantics

Type Source Name
gene UNIPROT SLC35G1
gene UNIPROT NAA50
drug DRUGBANK Quinidine
gene UNIPROT FBN1
pathway BSID Pertussis
disease DOID pertussis
disease MESH pertussis
gene UNIPROT RBM5
pathway BSID Tuberculosis
disease DOID tuberculosis
disease MESH tuberculosis
gene UNIPROT NCAPG2
drug DRUGBANK Amino acids
gene UNIPROT PRDM6
gene UNIPROT GAL
gene UNIPROT C2
gene UNIPROT BCS1L
drug DRUGBANK Streptomycin
drug DRUGBANK L-Glutamine
disease DOID lymphoma
disease MESH lymphoma
gene UNIPROT LITAF
disease MESH separated
gene UNIPROT LAT2
disease MESH embryo resorption
pathway BSID Fertilization
drug DRUGBANK Caffeine
drug DRUGBANK Midazolam
gene UNIPROT CYP3A4
gene UNIPROT NR4A3
drug DRUGBANK Gemfibrozil
drug DRUGBANK Orphenadrine
drug DRUGBANK Potassium cation
gene UNIPROT SMIM10L2A
gene UNIPROT SMIM10L2B
gene UNIPROT MOG
gene UNIPROT RTRAF
gene UNIPROT EIF2B5
disease DOID cle
disease DOID cle
drug DRUGBANK Choline
disease MESH multiple
disease MESH multi
disease DOID blastoma
disease DOID blastoma
gene UNIPROT ERBB2
gene UNIPROT NEU1
gene UNIPROT NEURL1
disease MESH growth
disease MESH tumor
disease DOID neuroblastoma
disease MESH neuroblastoma
disease MESH hemorrhage
gene UNIPROT CD36
gene UNIPROT FAT1
drug DRUGBANK Palmitic Acid
disease MESH liver steatosis
disease DOID Cmpd
gene UNIPROT NELFCD
gene UNIPROT SRXN1
gene UNIPROT SOD2
drug DRUGBANK Glutathione
gene UNIPROT GSTP1
gene UNIPROT NQO1
gene UNIPROT DECR1
gene UNIPROT GABPA
gene UNIPROT NFE2L2
pathway BSID Oxidative Damage
drug DRUGBANK Iodide
drug DRUGBANK Nitrogen
gene UNIPROT TSPO
gene UNIPROT CHRM3
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Rifampicin
disease DOID hepatoma
disease MESH hepatoma
gene UNIPROT TNF
disease MESH dif
drug DRUGBANK Activated charcoal
drug DRUGBANK Histidine
gene UNIPROT SPEF1
gene UNIPROT PDZK1
drug DRUGBANK Gold
pathway BSID Potassium Channels
gene UNIPROT KCNH2
gene UNIPROT ELAC1
disease MESH paralysis
gene UNIPROT CYP2B6
gene UNIPROT CYP2C8
gene UNIPROT CYP1A2
disease MESH drug interactions
gene UNIPROT PPIG
gene UNIPROT NOVA2
drug DRUGBANK Water
gene UNIPROT DEPP1
gene UNIPROT GOPC
gene UNIPROT SARDH
gene UNIPROT NR1I2
gene UNIPROT SRL
gene UNIPROT TNFSF13
gene UNIPROT ANP32B
gene UNIPROT TNFRSF10B
disease MESH defects
gene UNIPROT MBTPS1
drug DRUGBANK Fingolimod
disease MESH opportunistic infections
disease MESH relapses
gene UNIPROT DNMT1
gene UNIPROT CD69
gene UNIPROT CD5L
drug DRUGBANK Ademetionine
drug DRUGBANK Coenzyme M
drug DRUGBANK Dimethyl fumarate
disease MESH experimental autoimmune encephalomyelitis
disease DOID multiple sclerosis
disease MESH multiple sclerosis
disease DOID Demyelinating Disease
disease MESH Demyelinating Disease
gene UNIPROT CMKLR1

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