AI Article Synopsis

  • Lymphomas are common cancers with ongoing challenges in treatment, especially for patients whose tumors relapse after initial responses.
  • Research has identified a series of compounds called [1,2]oxazolo[5,4-e]isoindoles, which target the colchicine site of tubulin and show potential as effective treatments for refractory lymphomas.
  • Two specific compounds from this series demonstrated significant efficacy against various lymphoma types, achieving high inhibition of colchicine binding, indicating their promise as new therapeutic options.

Article Abstract

Lymphomas are among the ten most common cancers, and, although progress has been achieved in increasing survival, there is still an unmet need for more effective therapeutic approaches, including better options for patients with refractory tumors that initially respond but then relapse. The lack of effective alternative treatment options highlights the need to develop new therapeutic strategies capable of improving survival prospects for lymphoma patients. Herein, we describe the identification and exploration of the SAR of a series of [1,2]oxazolo[5,4-e]isoindoles as potent small molecules that bind to the colchicine site of tubulin and that have promise for the treatment of refractory lymphomas. Exploration of the chemical space of this class of compounds at the pyrrole moiety and at the [1,2]oxazole ring highlighted two compounds bearing a 3,5-dimethoxybenzyl and a 3,4,5-trimethoxybenzyl group as potent candidates and showed that structural modifications at the isoxazole moiety are generally not favorable for activity. The two best candidates showed efficacy against different lymphoma histotypes and displayed 88 and 80% inhibition of colchicine binding fitting well into the colchicine pocket, as demonstrated by X-ray crystallography TR-TTL-complexes, docking and thermodynamic analysis of the tubulin-colchicine complex structure. These results were confirmed by transcriptome data, thus indicating [1,2]oxazolo[5,4-e]isoindoles are promising candidates as antitubulin agents for the treatment of refractory lymphomas.

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http://dx.doi.org/10.1016/j.ejmech.2022.114744DOI Listing

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