MLN-3897   Click here for help

GtoPdb Ligand ID: 10750

Synonyms: AVE-9897 | AVE9897 | MLN3897
Compound class: Synthetic organic
Comment: MLN-3897 is a selective oral, small‐molecule receptor antagonist of CCR1 [1] and clinical lead that was developed for immunomodulatory potential and as a chemokine signalling inhibitor to reduce multiple myeloma (MM)-related osteolytic bone disease (blocking CCL3-CCR1-mediated signalling inhibits osteoclast formation and MM cell migration and survival) [3]. We show the chemical structure here without specified stereochemistry, as depicted in the 2016 article by Pusalkar et al. [1]. A stereo-specified enantiomer is claimed as (abs)-50 in MIllenium Pharmaceuticals' patent US20090286823 [4]. As there has been no formal disclosure of the name-to-structure, we show the 'flat' structure in good faith.

Analysis presented in a bioRxiv preprint (not peer reviewed) suggests that MLN-3897 impairs infection by SARS-CoV-2 in vitro [2].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 4
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 65.82
Molecular weight 532.25
XLogP 5.27
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES Clc1ccc(cc1)C1(O)CCN(CC1(C)C)CC/C=C\1/c2cc(ccc2OCc2c1cccn2)C(O)(C)C
Isomeric SMILES Clc1ccc(cc1)C1(O)CCN(CC1(C)C)CC/C=C\1/c2cc(ccc2OCc2c1cccn2)C(O)(C)C
InChI InChI=1S/C32H37ClN2O3/c1-30(2)21-35(18-15-32(30,37)22-9-12-24(33)13-10-22)17-6-8-25-26-7-5-16-34-28(26)20-38-29-14-11-23(19-27(25)29)31(3,4)36/h5,7-14,16,19,36-37H,6,15,17-18,20-21H2,1-4H3/b25-8+
InChI Key ZGFJFBOLVLFLLN-ZNLRHDTNSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Pusalkar S, Plesescu M, Milton M, Balani SK, Chowdhury S, Prakash S. (2016)
Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans.
Drug Metab Lett, 10 (1): 22-37. [PMID:26031460]
2. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, Burgstaller-Muehlbacher S, De Jesus PD, Teriete P, Hull MV et al.. (2020)
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
Nature, [Epub ahead of print]. DOI: 10.1038/s41586-020-2577-1
3. Vallet S, Raje N, Ishitsuka K, Hideshima T, Podar K, Chhetri S, Pozzi S, Breitkreutz I, Kiziltepe T, Yasui H et al.. (2007)
MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts.
Blood, 110 (10): 3744-52. [PMID:17715391]
4. Veibey OP, Anderson KC, Vallet S. (2009)
CCR1 Inhibitors useful for the treatment of multiple myeloma and other disorders.
Patent number: US20090286823A1. Assignee: Dana Farber Cancer Institute Inc; Millennium Pharmaceuticals Inc. Priority date: 17/12/2007. Publication date: 19/11/2009.
5. Vergunst CE, Gerlag DM, von Moltke L, Karol M, Wyant T, Chi X, Matzkin E, Leach T, Tak PP. (2009)
MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study.
Arthritis Rheum, 60 (12): 3572-81. [PMID:19950299]