Substituting hydrogen with deuterium in drug molecules is an appealing bioisosteric strategy for the generation of novel chemical entities in drug development. Optimizing lead compounds through deuteration has proven to be challenging and unpredictable, particularly for compounds with multiple metabolic sites. This study presents the pioneering achievement of substituting up to 19 hydrogen atoms with deuterium on 1,4-benzodiazepine-2,5-dione derivatives, shedding light on the structure-metabolism relationship and the impact of multiple deuterations on drug-like properties. Notably, the deuterated compound exhibited remarkable antitumor activity and demonstrated favorable drug-like properties as a drug candidate.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c00796 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Targeting EPHB2/ABL1 restores antitumor immunity in preclinical models of ependymoma.
Proc Natl Acad Sci U S A
January 2025
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Ependymoma (EPN) is a common form of brain tumor in children, often resistant to available cytotoxic therapies. Molecular profiling studies have led to a better understanding of EPN subtypes and revealed a critical role of oncogenes ZFTA-RELA fusion and EPHB2 in supratentorial ependymoma (ST-EPN). However, the immune system's role in tumor progression and response to therapy remains poorly understood.
View Article and Find Full Text PDFBivalent OX40 Aptamer and CpG as Dual Agonists for Cancer Immunotherapy.
ACS Appl Mater Interfaces
January 2025
College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
Cancer immunotherapy has revolutionized cancer treatment by harnessing the body's immune system to recognize and attack tumors. Over the past 25 years, the use of blocking antibodies has fundamentally transformed the landscape of cancer therapy. However, despite extensive research, agonist antibodies targeting costimulatory receptors such as ICOS, GITR, OX40, CD27, and 4-1BB have consistently underperformed in clinical trials over the past 15 years, failing to meet the anticipated success.
View Article and Find Full Text PDFThe Role of ROS and Its Sources in Tumorigenesis: Friend or Foe?
Adv Biol (Weinh)
January 2025
Department of General Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Ponicidin has demonstrated effectiveness against HCC by promoting mitochondria apoptosis and generating ROS through the stabilization of the Keap1-PGAM5 complex. However, ROS can exhibit both tumor-promoting and tumor-suppressing activities in cancers, and exhibit different effects depending on its source-mtROS vs non-mtROS. Additionally, since ROS from different sources possesses distinct functions, mitochondria-targeted antioxidants, and non-targeted antioxidants may have entirely different effects on cancer progression.
View Article and Find Full Text PDFThe combination of and mitigates DSS-induced colitis and attenuates colitis-associated tumorigenesis by modulating gut microbiota and reducing CD8 T cells in mice.
mSystems
January 2025
Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, Guizhou Medical University, Guiyang, China.
Unlabelled: The gut microbiota is closely associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). Probiotics such as (CB) or (AKK) have the potential to treat inflammatory bowel disease (IBD) or colorectal cancer (CRC). However, research on the combined therapeutic effects and immunomodulatory mechanisms of CB and AKK in treating IBD or CRC has never been studied.
View Article and Find Full Text PDFPeptide-Drug Conjugate for Therapeutic Reprogramming of Tumor-Associated Macrophages in Breast Cancer.
Adv Sci (Weinh)
January 2025
Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia.
In triple-negative breast cancer (TNBC), pro-tumoral macrophages promote metastasis and suppress the immune response. To target these cells, a previously identified CD206 (mannose receptor)-binding peptide, mUNO was engineered to enhance its affinity and proteolytic stability. The new rationally designed peptide, MACTIDE, includes a trypsin inhibitor loop, from the Sunflower Trypsin Inhibitor-I.
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!