A series of beta-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, -2, -3, and -9. This was achieved by exploiting subtle differences within the otherwise highly conserved S(1)(') binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P(1) and P(1)(') groups reduced the projected human clearance.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2007.11.086 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition of DPAGT1 suppresses HER2 shedding and trastuzumab resistance in human breast cancer.
J Clin Invest
July 2023
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine and.
Human epidermal growth factor receptor 2-targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance.
View Article and Find Full Text PDFRole of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer.
J Natl Cancer Inst
June 2019
Department of Pathology, College of Medicine.
Background: Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer.
Methods: The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases).
Relationships between serum HER2 ECD, TIMP-1 and clinical outcomes in Taiwanese breast cancer.
World J Surg Oncol
February 2012
Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan.
Background: Serum levels of the extracellular domain of HER2/neu (HER2 ECD) have been demonstrated to be associated with clinical outcomes. A disintegrin and metalloproteinase-10, a sheddase of HER2/neu, can drive cancer progression and its activity is inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1). However, elevated TIMP-1 expression has been associated with a poor prognosis of breast cancer.
View Article and Find Full Text PDFTargeted therapy in breast cancer: what's new?
Swiss Med Wkly
November 2011
Laboratory for Gynecological Oncology, University Hospital/Women's Hospital, Department of Biomedicine, University of Basel, CH.
Breast cancer is the most commonly diagnosed malignancy and one of the major causes of death among women. Breast cancer is also one of the most investigated diseases but whose biological features are still not well understood, several effective treating strategies having been explored in dealing with different types of advanced breast cancer, such as endocrine therapy and molecular targeted therapy. Trastuzumab is the first approved targeted anti-cancer agent to show an attractive response rate and outcomes in treating HER-2 positive metastatic breast cancer patients.
View Article and Find Full Text PDFTherapeutic strategies and mechanisms of tumorigenesis of HER2-overexpressing breast cancer.
Crit Rev Oncol Hematol
December 2012
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
The receptor tyrosine kinase HER2 is overexpressed in approximately 25% of breast cancers. HER2 acts as a signal amplifier for its siblings, namely three different transmembrane receptors that collectively bind with 11 distinct growth factors of the EGF family. Thus, overexpression of HER2 confers aggressive invasive growth in preclinical models and in patients.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!