Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.

Strategic design of lysine-targeted irreversible covalent NDM-1 inhibitors

New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein.Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.

Recent advances in periodontal regeneration: A biomaterial perspective

Periodontal disease(PD)is one of the most common inflammatory oral diseases,affecting approximately 47%of adults aged 30 years or older in the United States.If not treated properly,PD leads to degradation of periodontal tissues,causing tooth movement,and eventually tooth loss.Conventional clinical therapy for PD aims at eliminating infectious sources,and reducing inflammation to arrest disease progression,which cannot achieve the regeneration of lost periodontal tissues.Over the past two decades,various regenerative periodontal therapies,such as guided tissue regeneration(GTR),enamel matrix derivative,bone grafts,growth factor delivery,and the combination of cells and growth factors with matrix-based scaffolds have been developed to target the restoration of lost tooth-supporting tissues,including periodontal ligament,alveolar bone,and cementum.This review discusses recent progresses of periodontal regeneration using tissue-engineering and regenerative medicine approaches.Specifically,we focus on the advances of biomaterials and controlled drug delivery for periodontal regeneration in recent years.Special attention is given to the development of advanced bio-inspired scaffolding biomaterials and temporospatial control of multi-drug delivery for the regeneration of cementum-periodontal ligament-alveolar bone complex.Challenges and future perspectives are presented to provide inspiration for the design and development of innovative biomaterials and delivery system for new regenerative periodontal therapy.