Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth
Copyright © 2017. Published by Elsevier Ltd..
Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound's inhibition of cell growth led to measurements of survivin, Bcl-XL, p21WAF1/CIP1, and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 25(2017), 12 vom: 15. Juni, Seite 2995-3005 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhou, Donghui [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.08.2017 Date Revised 23.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2017.03.048 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM271247711 |
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| 500 | |a Date Revised 23.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017. Published by Elsevier Ltd. | ||
| 520 | |a Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound's inhibition of cell growth led to measurements of survivin, Bcl-XL, p21WAF1/CIP1, and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 650 | 7 | |a Small Molecule Libraries |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 700 | 1 | |a Springer, Maya Z |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, David |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Degang |e verfasserin |4 aut | |
| 700 | 1 | |a Hudmon, Andy |e verfasserin |4 aut | |
| 700 | 1 | |a Macleod, Kay F |e verfasserin |4 aut | |
| 700 | 1 | |a Meroueh, Samy O |e verfasserin |4 aut | |
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