Fluorescence polarization (FP) assays can be used to identify small-molecule inhibitors that bind to SH2 domain-containing proteins. We have developed FP assays by which to identify inhibitors of the SH2 domains of the two closely-related transcription factors STAT5a and STAT5b. Point mutation of selected amino acids in the putative binding site of the protein is a valuable tool by which to gain insight into the molecular mechanism of binding. In this chapter, we describe the cloning and application of point mutant proteins in order to transfer the binding preference of selected SH2 domain-binding STAT5b inhibitors to STAT5a, with results that highlight the importance of considering a role for residues outside the SH2 domain in contributing to the binding interactions of SH2 domain inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/978-1-0716-3393-9_12 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen.
Cell Chem Biol
December 2024
Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:
The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging.
View Article and Find Full Text PDFAnlotinib enhances the pro-apoptotic effect of APG-115 on acute myeloid leukemia cell lines by inhibiting the P13K/AKT signaling pathway.
Leuk Res
December 2024
Department of Hematopathy, Henan Institute of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China. Electronic address:
Background: APG-115 is a novel small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells. Anlotinib inhibits tumor angiogenesis and promotes apoptosis. In this study, we investigated the apoptotic effect and potential mechanism of APG-115 and anlotinib combination on AML cell lines with different p53 backgrounds.
View Article and Find Full Text PDFIncorporation of a rigid 1,3-diketone-containing fragment led to significantly improved AXL inhibitory activity: design, synthesis, and SAR of the anilinopyrimidine AXL inhibitors.
Mol Divers
December 2024
Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China.
Overexpressed AXL kinase is involved in various human malignancies, which incurs tumor progression, poor prognosis, and drug resistance. Suppression of the aberrant AXL axis with genetic tools or small-molecule inhibitors has achieved valid antitumor efficacies in both preclinical studies and clinical antitumor campaigns. Herein we will report the design, synthesis, and structure-activity relationship (SAR) exploration of a series of anilinopyrimidine type II AXL inhibitors.
View Article and Find Full Text PDFStrategy and Design of In Situ Activated Protein Hydrolysis Targeted Chimeras.
ACS Nano
December 2024
Faculty of Materials Science, Shenzhen MSU-BIT University, Shenzhen 518100, P. R. China.
Protein hydrolysis targeted chimeras (PROTACs) represent a different therapeutic approach, particularly relevant for overcoming challenges associated with traditional small molecule inhibitors. These challenges include targeting difficult proteins that are often deemed "undruggable" and addressing issues of acquired resistance. PROTACs employ the body's own E3 ubiquitin ligases to induce the degradation of specific proteins of interest (POIs) through the ubiquitin-proteasome pathway.
View Article and Find Full Text PDFA patent review of xanthine oxidase inhibitors (2021-present).
Expert Opin Ther Pat
December 2024
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China.
Introduction: Xanthine oxidase (XO) catalyzes the oxidation of both hypoxanthine and xanthine in the last two steps of the purine metabolic pathway, serving as a rate-limiting enzyme for uric acid production as well as a key target for the treatment of gout and other hyperuricemia-related conditions.
Areas Covered: This paper reviews XO inhibitors in patents from 2021 to the present. We summarize in detail the structural classes and characteristics, in vitro and in vivo biological results, and structure‒activity relationships of synthetic inhibitors, as well as the sources, specific structures, research methods, and biological activities of XO inhibitors from natural products.
Want 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!