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Registration Number

0225U004278, (0124U003835) , R & D reports

Title

Molecular design, synthesis and preclinical testing of new thiazole and thiazolidine derivatives with selective action on cells of myeloproliferative neoplasms

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Дослідження механізмів впливу вибраних селективних гетероциклічних сполук на клітини-моделі мієлопроліферативних новоутворень із мутаціями в генах JAK2, CALR, MPL, вивчення токсичності похідних in vivo

Head

Finiuk Nataliya S., Кандидат біологічних наук

Registration Date

27-11-2025

Organization

Institute of Cell Biology of the National Academy of Sciences of Ukraine

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The goal of the project is to create highly effective selective agents with targeted action for the treatment of myeloproliferative diseases with JAK2, CALR, and MPL gene mutations. For this purpose, the molecular design of new thiazole and 4-thiazolidinone derivatives will be developed, based on which compounds capable of selectively inhibiting malignant cells with JAK2, CALR, and MPL gene mutations will be synthesized.

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A series of novel heterocyclic small molecules based on non-condensed and condensed thiazole derivatives, as well as a set of new non-condensed/condensed bioisosteric hybrid thiazole-pyrazole molecules, were synthesized. Their structures were confirmed using ¹H, ¹³C, and 2D NMR spectroscopy, LC-MS, and X-ray crystallography. The affinity of compound Les-6650 for the N-domain of wild-type CALR (wt) was evaluated in comparison with a previously characterized ligand, the tetrasaccharide GlcMan3. The mean Vina scoring function values for GlcMan3 were −7.117 ± 0.013 kcal/mol, whereas for Les-6650 they were −6.254 ± 0.234 kcal/mol; the most favorable conformations of Les-6650 yielded scores of −6.841 and −6.737 kcal/mol. The predicted interaction energy of CALR wt with GlcMan3 was −463.50 ± 18.69 kJ/mol, and −241.06 ± 19.07 kJ/mol for Les-6650. Derivative MK-1118 exhibits selective activity toward MPN model cells harboring CALR ins5 and CALR del52 mutations. Derivatives Les-6788, Les-5549, and Les-6666 were found to reduce the viability of UT-7/GM Jak2 V617F (GFP) cells. Les-6788 and Les-6776 demonstrated stronger toxicity toward UT-7/TPO MPL W515K cells than toward cells lacking the MPL W515K mutation. At the same time, Les-6788, Les-5549, Les-6776, and Les-6666 did not exhibit significant toxicity toward lymphocytes and granulocytes from healthy donors (IC₅₀ > 50 μM). Compounds MK-1118 and Les-6650 increased the level of wild-type CALR protein in Ba/F3 MPL CALR ins5 and Ba/F3 MPL CALR del52 cells, which may indicate partial restoration of its physiological function. No increase in PI3K, phosphorylated Jak2, STAT5, or Akt levels was observed. Les-6650 and MK-1118 induced apoptosis in Ba/F3 CALR del52 and Ba/F3 MPL CALR ins5 cells. Les-6650 (30, 60, and 120 mg/kg) demonstrated a favorable safety profile, characterized by minimal changes in body weight (≤6%), stable leukopoiesis and erythropoiesis, and normal organ-to-body weight ratios.

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Serhiy M. Holota
Yuliia S. Kozak
Yulian T. Konechnyi
Iryna I. Ivasechko
Nataliya S. Finiuk
Ihor M. Yushyn

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2025-11-27