Targeting BCL6 in DLBCL: The Impact of PROTAC Degraders in Preclinical Studies

Researchers have developed a specific and potent BCL6-targeting PROTAC degrader, ARVN-71228, which has shown to be effective in inhibiting the growth of various diffuse large B-cell lymphoma (DLBCL) cell lines, both in vitro and in vivo. The compound has been found to be particularly effective in models of high-risk (HR) aggressive double- and triple-hit (DH/TH) lymphomas, which have historically had poor outcomes.

In vitro studies have shown that a significant number of germinal center B-cell (GCB) and activated B-cell (ABC) DLBCL cell lines are sensitive to BCL6 PROTAC treatment, indicating that the dependence on BCL6 is not limited to BCL6-mutated DLBCLs. The advanced degrader ARVN-71228 has demonstrated over 95% maximum BCL6 degradation at a concentration of less than 1 nM in the OCI-Ly1 model, leading to cell cycle arrest and increased apoptosis.

Medicinal chemistry efforts have led to the creation of orally bioavailable BCL6 PROTAC degraders suitable for in vivo dosing. Time-course studies have shown that BCL6 levels can be reduced by over 95% within four hours, and this reduction is sustained for up to 24 hours. The degradation of BCL6 has also been associated with the derepression of genes such as BLIMP1 and PTPN6, which are normally repressed by BCL6.

In vivo, ARVN-71228 has been shown to induce regressions in the GCB OCI-Ly1 CDX model. Future research aims to explore rational drug combinations with BCL6 PROTAC degraders to identify synergistic pathways, particularly for HR-DLBCL subtypes where there is a significant unmet medical need.

The disclosures section indicates that several authors are currently employed by and hold equity in Arvinas, a publicly-traded company, with some having divested equity in the past 24 months.