Three first-in-class small molecular inhibitors that target SOX11 have demonstrated antitumour activity in vitro, and in ex vivo patient-derived ibrutinib-resistant models.
Mantle cell lymphoma (MCL) is typically a fatal subtype of Non-Hodgkin lymphoma, and novel treatment are needed to treat patients with relapsed disease. Characteristic of MCL, SOX11 transcription factor is overexpressed in the majority of MCL cases, and represents a potential therapeutic target. Despite the fact that transcription factors are widely thought to be untargetable, SOX11 binds to a minor groove of DNA, the cavity of which, is targetable. Understanding this, Jatiani et al., used in silico predictions to identify 3 small molecule inhibitors that may be capable of binding to SOX11.
“The SOX11 protein, which is expressed in up to 90% of patients with MCL, is an attractive target for therapy,” said senior author Samir Parekh, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai. “But until now, no small molecule inhibitor had been identified. We discovered three structurally related compounds which are able to bind to the oncogene, perturb its interaction with DNA and, through their anti-MCL cytotoxicity, kill lymphoma cells with remarkable efficiency.”
With the potential inhibitors identified, known as compounds E, R and T, the antitumour activity of these compounds was then evaluated in patient-derived xenograft mouse models. In the study, peripheral blood was collected from 4 patients with an acquired resistance to ibrutinib. Peripheral blood mononuclear cells were then engrafted with ibrutinib-resistant MCL cells and delivered intravenously into NSG mice. Compounds E and R were found to have robust inhibitory activity in SOX11-positive cells, with an IC50 between 12μM to 16μM, and conversely, an IC50 ranging from 14μM to 34μM in SOX11-negative cells. Compound R was then evaluated further in ibrutinib-resistant MCL models, finding that the compound resulted in MCL cytotoxic activity in all three patients who were positive for SOX11.
“These small molecule inhibitors could also be useful tools for understanding the pathogenesis of other malignancies that can be traced to SOX11, including epithelial ovarian tumors, medulloblastoma, gliomas, and basal-like breast cancer,” said Parekh. “Many transcription factors exist in a variety of tumors that could be targeted by scientists, and what we’ve demonstrated through our work is that there is indeed an effective way to make them druggable,” Parekh concluded. Moving forward, these experimental inhibitors represent a new class of small molecule inhibitor, and warrant further investigation, and may be applicable to oncogenic diseases other than MCL.
Reference
Jatiani et al., SOX11 inhibitors are cytotoxic in mantle cell lymphoma. Clin Cancer Res. 2021; [epub].
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