Linker Variation and Structure-Activity Relationship Analyses of Carboxylic Acid-based Small Molecule STAT3 Inhibitors.

The molecular determinants for the activities of the reported benzoic acid (SH4-54), salicylic acid (BP-1-102), and benzohydroxamic acid (SH5-07)-based STAT3 inhibitors were investigated to design optimized analogues. All three leads are based on an N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities and the CH2 group of the glycinamide scaffold were separately modified. The replacement of the pentafluorobenzene or cyclohexylbenzene, or replacing the benzene ring of the aromatic carboxylic or hydroxamic acid motif with heterocyclic components (containing nitrogen and oxygen elements) all decreased potency. Notably, the Ala-linker analogues, 1a and 2v, and the Pro-based derivative 5d, all with (R)-configuration at the chiral center, had improved inhibitory activity and selectivity against STAT3 DNA-binding activity in vitro, with IC50 of 3.0 ± 0.9, 1.80 ± 0.94, and 2.4 ± 0.2 µM, respectively. Compounds 1a, 2v, 5d, and other analogues inhibited constitutive STAT3 phosphorylation and activation in human breast cancer and melanoma lines, and blocked tumor cell viability, growth, colony formation, and migration in vitro. Pro-based analogue, 5h, with a relatively polar tetrahydropyranyl (THP) ring, instead of the cyclohexyl, showed improved permeability. In general, the (R)-configuration Pro-based analogs showed the overall best profile, including physicochemical properties (e.g., microsomal metabolic stability, Caco-2 permeability), and in particular, 5d showed improved tumor-cell specificity.

Hair product use and breast cancer risk among African American and White women.

Exposures to carcinogens in hair products have been explored as breast cancer risk factors, yielding equivocal findings. We examined hair product use (hair dyes, chemical relaxers and cholesterol or placenta-containing conditioners) among African American (AA) and White women, and explored associations with breast cancer. Multivariable-adjusted models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to describe the associations of interest among 2280 cases (1508 AA and 772 White) and 2005 controls (1290 AA and 715 White). Among controls, hair dye use was more common among Whites than AAs (58 versus 30%), while relaxer (88 versus 5%) and deep conditioner use (59 versus 6%) was more common among AAs. Among AAs, use of dark hair dye shades was associated with increased breast cancer risk (OR = 1.51, 95% CI: 1.20-1.90) and use of dark shades (OR = 1.72, 95% CI: 1.30-2.26) and higher frequency of use (OR = 1.36, 95% CI: 1.01-1.84) were associated with ER+ disease. Among Whites, relaxer use (OR = 1.74, 95% CI: 1.11-2.74) and dual use of relaxers and hair dyes (OR = 2.40, 95% CI: 1.35-4.27) was associated with breast cancer; use of dark hair dyes was associated with increased ER+ disease (OR = 1.54, 95% CI: 1.01-2.33), and relaxer use was associated with increased ER- disease (OR = 2.56, 95% CI: 1.06-6.16). These novel findings provide support a relationship between the use of some hair products and breast cancer. Further examinations of hair products as important exposures contributing to breast cancer carcinogenesis are necessary.

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma.

Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRß. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.