Three first-in-class, SOX11 small molecule inhibitors demonstrated on-target antitumor activity in mantle cell lymphoma cell lines and in patient-derived ibrutinib-resistant models ex vivo.
Three first-in-class, SOX11 small molecule inhibitors demonstrated on-target antitumor activity in mantle cell lymphoma (MCL) cell lines and in patient-derived ibrutinib (Imbruvica)-resistant models ex vivo, according to findings from a study published in Clinical Cancer Research.1
All 3 compounds––E, R, and T––were found to bind SOX11-DNA binding domain (DBD) with micromolar affinities. However, the cellular growth inhibition and biochemical activity of each compound was not the result of direct binding to DNA, indicating that there was no interference between the inhibitors and DNA unwinding activity.
“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.2 “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.”
MCL is typically associated with poor prognosis and novel treatments for patients with relapsed disease represent a large unmet need.
Although SOX11 represents a potential therapeutic target, transcription factors such as SOX11 are considered undruggable because of their lack of binding pockets and grooves for small molecules. However, the ability of SOX11 to bind to the minor groove of DNA led investigators to hypothesize that there may be cavities at the protein-DNA junction that allow for targeted approaches.
To that end, investigators tested structurally relevant compounds that could elicit SOX11-specific antitumor activity in MCL models.
In the study, primary MCL cells were collected from the peripheral blood of 4 patients with acquired resistance to ibrutinib. The patient-derived xenograft mouse model was created by engrafting peripheral blood mononuclear cells from patient 2 with acquired ibrutinib-resistant MCL intravenously into NSG mice.
A total of 5 compounds (A-E) were purchased and evaluated in a SOX11-expressing MCL cell line and a SOX11-negative MCL cell line. Compound E demonstrated selective proliferative inhibition of the SOX11-expressing MCL cell line, suggesting that the agent’s mechanism of action is dependent on SOX11 binding.
Structural analogs that had at least 80% similarity to compound E were then identified, from which 2 compounds (R and T) were purchased for further study.
Additional findings indicated that compound E and R had robust inhibitory activity in SOX11-positive cells at an IC50 ranging from 12μM to 16μM compared with SOX11-negative cells at an IC50 ranging from 14μM to 34μM.
Compound R was then selected for evaluation in ibrutinib-resistant primary MCL models. Three of 4 of these patients tested positive for SOX11. Treatment with compound R led to cytotoxic activity in the 3 SOX11-positive models.
“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.