Transcriptome and computational analysis assess the anti-tubulin activity of [1,2]oxazole derivatives in lymphoma

Background: Anti-tubulin agents are widely used in the treatment of lymphoma and included important chemotherapy schemes (R-CHOP, ABVD, BEACOP) as well innovative therapeutic approaches utilizing antibody-drug conjugates (ADCs) such brentuximab vedotin polatuzumab vedotin. Recently, we have devoted our efforts to investigation a large family [1,2]oxazole-based derivatives that showed anti-proliferative activity several models, with IC50 values between low micromolar nanomolar range. High inhibition tubulin polymerization due strong interactions colchicine-binding site was confirmed by computational studies colchicine binding tubulin. We now present transcriptome changes induced best candidate this (SIX2-F). Material methods: To unravel gene expression changes, MINO cell line exposed DMSO or 100 nM compound for 8, 12 24 hours transcripts analyzed RNA-Seq. The mode elucidated X-ray crystallographic studies, using T2R-TTL protein complex composed two αβ-tubulin (T2) dimers, stathmin-like RB3 (R) tyrosine ligase (TTL). Each dimer contained an accessible site, termed β1 β2. Finally, docking poses molecular dynamics simulations (MDs) were generated towards 4O2B PDB model. Results: caused SIX2-F revealed significant upregulation genes related either spindle microtubule assembly G2/M transition. top upregulated CCNB1 (cyclin B1), CCNB2 B2), AURKA (aurora kinase A), PLK1 (Polo-like 1), CENPA (centromere CENPE E) BIRC5 (survivin), while involved transcription DNA replication downregulated. In T2R-TTL-ligand structure, large, shaped difference density within observed SIX2-F, proving ligand bound. particular, βT7 αT5 loops flipped accommodate compound. Docking calculations well-fitted pocket (G-Score = −9.71 Kcal/mol), directing methoxybenzyl moiety C241. further stabilized means hydrophobic residues A180, L242, L248, L250, L252, L255, A316, I317 A354. Conclusions: Transcriptome overlapped those reported other inhibitors. These data, supported its crystal structure tubulin, validated anti-tubulin agent promising refractory lymphomas. Conflict interest: Ownership: Patent