Jul 2026· Journal of Medicinal Chemistry· Vol 69, pp. 18553-18579· 1 citation· 44 references
Medicine
TL;DR
A highly selective small-molecule KIT inhibitor is described that exhibits excellent broad kinome selectivity, with a selectivity score of S(50%) = 0.003, demonstrated promising in vivo therapeutic efficacy in an SCF-driven acute cutaneous anaphylaxis model in rodents.
Abstract
Mast cells play critical roles in the pathogenesis of many allergic and inflammatory diseases. KIT, a receptor tyrosine kinase, is a crucial regulator of mast cells and, in consequence, the modulation of mast cells through KIT inhibition presents a promising therapeutic approach for treating a range of chronic diseases. Clinical applications of small-molecule KIT inhibitors have been limited to oncology due to adverse effects associated with poor kinome selectivity. Here, we describe a highly selective small-molecule KIT inhibitor (7) that exhibits excellent broad kinome selectivity, with a selectivity score of S(50%) = 0.003. Data-driven investigations of structure-activity relationships and careful modulation of physicochemical properties yielded improvements in potency, selectivity, and metabolic stability. Compound 7 demonstrated promising in vivo therapeutic efficacy in an SCF-driven acute cutaneous anaphylaxis model in rodents.
Relevant cytokines involved in inflammatory processes in asthma and Chronic Obstructive Pulmonary Disease (COPD) signal through the Janus kinase (JAK) proteins. Therefore, a JAK inhibitor blocking multiple cytokine signaling pathways constitutes a potential new anti-inflammatory therapy for these diseases. Herein is de...
Jordi Bach, D. Perez, C. Esteve et al.· Journal of Medicinal Chemist...· 0 citations
The EP4 receptor (EP4R) has emerged as a promising target in immuno-oncology due to its role in modulating tumor immunity and inflammation. Here, we describe the discovery and preclinical development of DT-9081, a clinical candidate EP4R-antagonist that has completed a phase I monotherapy trial for the treatment of s...
Anne-Laure Blayo, G. Hommet, Mickael Fer et al.· Journal of Medicinal Chemist...· 1 citation
PKMYT1 mediates the inhibitory phosphorylation of CDK1 and represents a promising synthetic lethal target in p53-deficient or CCNE1-amplified malignancies. A series of PKMYT1 inhibitors featuring a novel monocyclic pyridine core structure was discovered, exhibiting improved selectivity and enhanced drug-like properties...
The design, synthesis, and biological evaluation of a novel series of type II c-Met inhibitors bearing α-amino acid-derived linkers and a morpholinopropoxy quinoline scaffold position compound 41 as a promising lead for the development of next-generation, tolerable c-Met targeted therapeutics.
Zhong-Yuan Wang, Yi-Wei Zhang, Yun-Feng Wang et al.· European journal of medicina...· 0 citations
This study successfully designed and synthesized a novel series of quinazoline-chalcone hybrids, creating new chemical entities to exploit potential synergistic antitumor effects and indicated promising drug-like properties and safety profiles.
Yingnuo Wang, Jurang Li, Chun-Meng Li et al.· Journal of the Serbian Chemi...· 0 citations
The development of compound 45 is reported, a novel imidazopyrazine derivative acting as a long-lasting, dual A2A/A2B receptor antagonist with nanomolar in vitro potency, providing high oral bioavailability and systemic exposure across multiple preclinical species.
M. Gałęzowski, M. Kujawa, A. Bobowska et al.· Journal of Medicinal Chemist...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
