Design and synthesis of novel diaminoquinazolines with in vivo efficacy for beta-catenin/T-cell transcriptional factor 4 pathway inhibition. | LitMetric
Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA.
Published: January 2010
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Article Abstract
We are introducing a novel series of 2,4-diaminoquinazolines as beta-catenin/Tcf4 inhibitors which were identified by ligand-based design. Here we elucidate the SAR of this series and explain how we were able to improve key molecular properties such as solubility and cLogP leading to compound 9. Analogue 9 exhibited better biological activity and improved physical and pharmacological properties relative to the HTS hit 49. Furthermore, 9 demonstrated good cell growth inhibition against several human colorectal cancer lines such as LoVo and HT29. In addition, treatment with compound 9 led to gene expression changes that overlapped significantly with the transcriptional profile resulting from the pathway inhibition by siRNA knockdown of beta-catenin or Tcf4. Subsequently, 9 was tested for efficacy in a beta-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume.
Microplastics (MPs) are a growing problem worldwide. Soils are long-term storage sinks of MPs because of the many pathways they enter the soil and their long degradation period. Knowing how MPs influence soil organisms, the effects of organisms on the fate of MPs, and what this means for soil additions, losses, transformations, and translocations is paramount.
Pulmonary hypertension (PH) is a progressive disease characterized by vascular reHypoxiaing, endothelial cell dysfunction, and inflammation. Liver Kinase B1 (LKB1, also known as STK11) is a central regulator of cell polarity and energy homeostasis. However, its specific role and mechanism of action in PH remain unclear.
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