With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm400778dDOI Listing

Publication Analysis

Top Keywords

selective kinase
8
kinase inhibitor
8
targeting pan-raf
8
pan-raf inhibition
8
c-7-substituted 13-benzothiazole
8
13-benzothiazole derivatives
8
discovery selective
4
inhibitor tak-632
4
tak-632 targeting
4
inhibition design
4

Similar Publications

Advancing therapeutic frontiers: a pipeline of novel drugs for luminal and perianal Crohn's disease management.

Therap Adv Gastroenterol

December 2024

Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, Padua 35128, Italy.

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria.

View Article and Find Full Text PDF

Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome.

J Med Chem

December 2024

Medicines Discovery Institute, School of Biosciences, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, U.K.

LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS.

View Article and Find Full Text PDF

An electrochemical aptasensor for the detection of bisphenol A based on triple signal amplification assisted by gold nanoparticles, hemin/G-quadruplex DNAzyme, and exonuclease I.

Mikrochim Acta

December 2024

Key Laboratory for Analytical Science of Food Safety and Biology, MOE, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou, 350108, China.

A triple signal amplified electrochemical aptasensor for the detection of bisphenol A (BPA) was developed for the first time based on gold nanoparticles (AuNPs), hemin/G-quadruplex DNAzyme, and exonuclease I (Exo I) assisted amplification strategies. The BPA aptamer (Apt) hybridized with the capture probe (CP) was fixed on the gold electrode (GE) to form the double-stranded DNA (dsDNA) structure. When BPA was present, the Apt was detached from the GE surface by specific recognition between the BPA and Apt, forming BPA-Apt complexes in solution.

View Article and Find Full Text PDF

IL-1β stimulates a novel axis within the NFκB pathway in endothelial cells regulated by IKKα and TAK-1.

Biochem Pharmacol

December 2024

Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK. Electronic address:

In this study we examined the activation of the non-canonical NFκB signalling pathway in endothelial cells. In HUVECs, LIGHT stimulated a delayed induction of serine 866/870 p100 phosphorylation linked to p52 NFκB formation. Surprisingly, the canonical ligand, IL-1β, stimulated a rapid phosphorylation or p100 which was not associated with p52 formation.

View Article and Find Full Text PDF

Background/aims: Upadacitinib is a novel selective Janus kinase inhibitor approved for use in ulcerative colitis. Clinical trials had rigorous criteria and excluded many patient subgroups. Given limited real-world effectiveness data, we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population.

View Article and Find Full Text PDF

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!