Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth.
Bioorg Med Chem
; 25(12): 2995-3005, 2017 06 15.
Article
em En
| MEDLINE
| ID: mdl-28438385
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
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Proliferação de Células
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Fator de Transcrição STAT3
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Neoplasias de Mama Triplo Negativas
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Antineoplásicos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article