NEW YORK (Reuters Health) – Newly discovered inhibitors of SOX11, a transcription factor that seems to be a driver of mantle cell lymphoma (MCL), showed promise in laboratory experiments.
“Our lab previously developed a mouse model in which SOX11 overexpression results in MCL, suggesting this is a main driver of this disease, and inhibiting SOX11 may be therapeutically useful,” Dr. Samir Parekh of the Icahn School of Medicine at Mount Sinai in New York City told Reuters Health by email. “However, SOX11 inhibitors did not previously exist, and we therefore conducted this study to screen and rationally develop (them) based on their structure and interaction with DNA.”
SOX11 had been considered “undruggable,” he explained, “because in contrast to other proteins, such as kinases, they lack pockets where small molecules can be designed to bind and inhibit function. The finding that molecules from our initial screen indeed abrogated SOX11-DNA binding and caused anti-MCL cytotoxicity, even in cells obtained from ibrutinib-resistant patients, was a surprise.”
Dr. Parekh and colleagues hypothesized that the ability of SOX11 to bind to the minor groove of DNA meant there might be cavities at the protein-DNA interface that are amenable to targeting by small molecules.
As reported in Clinical Cancer Research, the team screened more than 12 million compounds at the SOX11 surface that interact with DNA, and identified numerous small molecules predicted to perturb the SOX11-DNA interaction, thereby blocking the development of MCL.
Using a combination of in silico predictions and experimental validations, they confirmed that three structurally related compounds bind SOX11, perturb its interaction with DNA and effect SOX11-specific anti-MCL cytotoxicity.
One of the three inhibitors showed anti-MCL cytotoxicity in a human cell line, as well as inhibition of BTK phosphorylation, which is part of a signaling cascade that triggers the malignant transformation of B lymphocytes into MCL.
Further, as Dr. Parekh noted, the SOX11 inhibitor induced cytotoxicity specifically in SOX11-positive ibrutinib-resistant MCL patient samples, and inhibited BTK phosphorylation in a xenograft mouse model derived from one of these patients.
“Taken together,” the authors state, “our results provide a foundation for therapeutically targeting SOX11 in MCL by a novel class of small molecules.”
Dr. Parekh said, “We are developing compounds that can ultimately go to human trials and help MCL patients failing current therapies, including ibrutinib. There are several transcription factors that are oncogenic and have previously not been considered as drug targets. With new scientific approaches, these may be excellent choices for drug development in the future.”
Dr. Alexey Danilov, Associate Director, City of Hope’s Toni Stephenson Lymphoma Center, commented in an email to Reuters Health, “Molecules targeting SOX11 show strong pre-clinical promise and further bench-to-bedside translation of these compounds is being eagerly awaited.”
“It would be important to investigate the role of SOX11 outside of B-cell receptor signaling, followed by rational design of therapeutic combinations,” he said. “Furthermore, SOX11 is a transcription factor, and thus is a difficult target. Additional optimization of the molecule may be necessary prior to transition to clinical trials.”
Dr. Francisco Hernandez-Ilizaliturri, Chief of Lymphoma Section at Roswell Park Comprehensive Cancer Center in Buffalo, New York, also commented by email. “Their findings are very relevant as we continue to search for novel agents with promising activity in relapsed/refractory MCL. SOX-11 inhibitors could be part of a new generation of targeted agents.”
He added, “Additional studies that are necessary to further determine the clinical applicability of SOX-11 inhibitors include in vivo experiments testing their anti-tumor activity in MCL pre-clinical models and toxicity studies to evaluate their safety and potential toxicities that could be seen if they are administered in patients.”
SOURCE: https://bit.ly/3qFCg6i Clinical Cancer Research, online June 22, 2021.
Source: Read Full Article