Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells

Souvik Banerjee, Derek D. Norman, Sue Lee, Abby L. Parrill, Truc Chi T. Pham, Daniel L. Baker, Gabor Tigyi, Duane Miller

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC 50 ∼ 32 nM; 3b, IC 50 ∼ 9 nM; and 14, IC 50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC 50 ∼ 84 nM), lack inhibitory action on ENPP6 and ENPP7 but possess weak antagonist action specific to the LPA 1 G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic resistance of 4T1 breast cancer stem-like cells to paclitaxel and significantly reduced B16 melanoma metastasis in vivo.

Original languageEnglish (US)
Pages (from-to)1309-1324
Number of pages16
JournalJournal of Medicinal Chemistry
Volume60
Issue number4
DOIs
StatePublished - Feb 23 2017

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Neoplastic Stem Cells
Sulfonamides
Benzene
Melanoma
Breast Neoplasms
Neoplasm Metastasis
Experimental Melanomas
Acids
Structure-Activity Relationship
G-Protein-Coupled Receptors
Paclitaxel
Computer Simulation
Lipids
lysophosphatidic acid
In Vitro Techniques
Lead

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells. / Banerjee, Souvik; Norman, Derek D.; Lee, Sue; Parrill, Abby L.; Pham, Truc Chi T.; Baker, Daniel L.; Tigyi, Gabor; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 60, No. 4, 23.02.2017, p. 1309-1324.

Research output: Contribution to journalArticle

Banerjee, Souvik ; Norman, Derek D. ; Lee, Sue ; Parrill, Abby L. ; Pham, Truc Chi T. ; Baker, Daniel L. ; Tigyi, Gabor ; Miller, Duane. / Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 4. pp. 1309-1324.
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AB - Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC 50 ∼ 32 nM; 3b, IC 50 ∼ 9 nM; and 14, IC 50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC 50 ∼ 84 nM), lack inhibitory action on ENPP6 and ENPP7 but possess weak antagonist action specific to the LPA 1 G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic resistance of 4T1 breast cancer stem-like cells to paclitaxel and significantly reduced B16 melanoma metastasis in vivo.

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