What is the role of SGI-1776 in inhibiting Pim kinases in mantle cell lymphoma (MCL)?

Label:chem

Topic
SGI-1776 is a small molecule inhibitor of Pim kinases, which are serine/threonine/tyrosine kinases involved in transcription, translation, cell cycle progression, and survival pathways. Pim kinases are overexpressed in B-cell malignancies such as MCL, making them potential therapeutic targets.
Answer
SGI-1776 selectively binds to the ATP-binding site of Pim-1 and inhibits all three Pim kinases (Pim-1, Pim-2, and Pim-3) with IC50 values of 7 nM, 363 nM, and 69 nM, respectively. It induces apoptosis in MCL cell lines and primary cells by inhibiting the phosphorylation of key Pim kinase targets such as c-Myc (Ser62), Histone H3 (Ser10), Bad (Ser112), and 4E-BP1 (Thr37/46). This inhibition disrupts transcriptional and translational processes, leading to decreased levels of short-lived proteins like Mcl-1 and cyclin D1, ultimately promoting cell death.
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