Registration Number
0226U002209,
(0125U002857)
, R & D reports
Title
Preclinical study of the antifibrotic effect of novel heterocyclic inhibitors of TGF-b, JAK1 and JAK2 in scleroderma models
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Оцінка антифіброзної активності in vitro
Head
Ivasechko Iryna I., Доктор філософії
Registration Date
11-02-2026
Organization
Institute of Cell Biology of the National Academy of Sciences of Ukraine
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The main goal of the research planned in the project is to study the antifibrotic activity of new heterocyclic compounds, inhibitors of transforming growth factor beta (TGF-β), which plays a key role in the pathogenesis of fibrosis, Janus kinases 1 and 2 (JAK1 and JAK2), which in scleroderma contribute to inflammation, fibroblast activation, and collagen deposition in mono- and combination therapy of scleroderma/skin fibrosis, to evaluate their efficacy, selectivity, and safety in cell and animal models, and to determine optimal combinations of these inhibitors to create innovative therapeutic strategies aimed at reducing fibrotic changes and restoring tissue functions.
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PRECLINICAL STUDY OF THE ANTIFIBROUS EFFECT OF NEW HETEROCYCLIC INHIBITORS TGF-B, JAK1 AND JAK2 IN SCLERODERMA MODELS Project registration number: 0210/13-2025. Grant agreement number: No. 40/10-2025 dated July 1, 2025, KPKV 6541030 (fundamental research, special fund). Funding for 2025 – UAH 130 thousand. Stage I “Assessment of antifibrotic activity in vitro”.
The aim of the work is to study the antifibrotic activity of new heterocyclic compounds, inhibitors of transforming growth factor beta (TGF-β), which plays a key role in the pathogenesis of fibrosis, Janus kinases 1 and 2 (JAK1 and JAK2), which in scleroderma contribute to inflammation, fibroblast activation and collagen deposition in mono- and combination therapy of scleroderma/skin fibrosis, to evaluate their efficacy, selectivity and safety in cell and animal models, as well as to determine the optimal combinations of these inhibitors to create innovative therapeutic strategies aimed at reducing fibrotic changes and restoring tissue functions.
In the initial in vitro screening on BALB/3T3 and NIH/3T3 fibroblasts in fibrosis models (TGF-β, bleomycin, hypoxia-induced), compound 1 (thiopyrano[2,3-d]thiazole derivative) was the leader, reducing collagen synthesis by 22.25% at 0.1 μM (parallel incubation with TGF-β), by 6–8% in the therapeutic regimen and by 15.66% in the hypoxia model, with high cell survival (84–94%). Other compounds in the series (10, 14) showed moderate reductions (8–19%), mainly in the TGF-β model. JAK1/2 inhibitory compounds ylidene-4-((3-methyl-1H-pyrazol-5-yl)amino)thiazole derivatives (19–21) had weak or no effect. Measurement of secreted collagen confirmed a moderate effect on secretion (8–17%), but a stronger effect on deposition (Sirius Red). Combinations (1 + 19) did not outperform monotherapy, but showed an additive effect. Microscopy and Western blot confirmed the reduction of collagen and the induction of apoptosis of activated fibroblasts by compound 1.
Product Description
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Yuliia S. Kozak
Nazar O. Manko
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2026-02-11
