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Registration Number

0224U032926, (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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Молекулярне моделювання, синтез похідних тіазолу і тіазолідину, відбір сполук із селективністю дії на клітини мієлопроліферативних новоутворень з мутаціями в генах JAK2, CALR, MPL

Head

Finiuk Nataliya S., Кандидат біологічних наук

Registration Date

11-12-2024

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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 Compounds with affinity for mutated CALR, JAK2, and MPL proteins were identified, as confirmed by molecular docking. Les-6650 demonstrated high MolDock Score affinity for CALR del52 (-88.7464), Les-3941 for JAK2 V617F (-178.571), and MPL W515L/R (-113.751 and -240.016, respectively). Compared to known drugs Delgocitinib and Baricitinib, the synthesized compounds showed competitive results, indicating their potential in treating myeloproliferative neoplasms (MPNs). ADMET calculations suggest that Les-6650, Les-1495, Les-5463, and Les-4339 comply with key medicinal chemistry rules, including Lipinski’s Rule of Five, which predicts good oral bioavailability. Les-6650 stands out due to balanced parameters such as molecular weight, topological polar surface area (TPSA), and Fsp3, indicating its potential for solubility and absorption. Over 100 new derivatives of thiazolidine and related heterocyclic systems were synthesized using cyclocondensation, azo-coupling, hydrolysis, and Claisen-Schmidt reactions. The ¹H- and ¹³C-NMR spectroscopy, chromatographic-mass spectrometry, and X-ray crystallography were used to confirm the molecular structures of designed compounds. Les-6650, Les-4339, Les-1495, and Les-5463 exhibit selective toxicity toward MPN cell models with CALR mutations (del52, ins5). Les-1132 and Les-4339 showed selective action on model cells with JAK2 V617F and MPL (TPOR) mutations. At the same time, these compounds demonstrated no significant toxicity toward normal or tumor cells of other types (IC50 >50 μM). New thiazole derivatives (Les-6547, Les-6557, Les-6563, Les-6564) were identified that selectively suppress the viability of colorectal cancer cells while showing low toxicity toward pseudo-normal cell lines. The obtained results confirm the potential of the synthesized compounds for further investigation as therapeutic agents for the treatment of MPNs and certain cancers, particularly those with CALR, JAK2, and MPL mutations.

Product Description

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Holota Serhii M.
Kozak Yuliia S.
Konechnyi Yulian T.
Starykovych Maryna O.
Finiuk Nataliia S.
Yushyn Ihor M.

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2024-12-11