Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth

Donghui Zhou, Maya Z. Springer, David Xu, Degang Liu, Andy Hudmon, Kay F. Macleod, Samy Meroueh

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry
DOIs
StateAccepted/In press - Jan 24 2017

Fingerprint

Autophagy
Triple Negative Breast Neoplasms
Tumors
Cyclin A2
Bone
Chemical activation
Cells
Leucine Zippers
Phosphorylation
Molecules
Polypharmacology
Cell growth
Progesterone Receptors
Phosphotransferases
Growth
Bone Marrow
Estrogen Receptors
Protein-Tyrosine Kinases
Breast Neoplasms
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth. / Zhou, Donghui; Springer, Maya Z.; Xu, David; Liu, Degang; Hudmon, Andy; Macleod, Kay F.; Meroueh, Samy.

In: Bioorganic and Medicinal Chemistry, 24.01.2017.

Research output: Contribution to journalArticle

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