Abstract
The BCL6 transcription repressor (B-cell lymphoma 6, BCL6) protein has been shown to be a key molecular driver of diffuse large B-cell lymphoma (DLBCL). Somatic mutations of the BCL6 gene include gross- or cryptic-chromosome translocations and point mutations that have been shown to result in the deregulation of BCL6 expression. These BCL6 abnormalities also contribute to a subgroup of high-risk (HR) aggressive double- and triple-hit (DH/TH) lymphomas with very poor outcomes. We have developed highly specific, potent and orally bioavailable BCL6 PROteolysis TArgeting Chimera (PROTAC TM) degraders that demonstrate potent in-vitro and in-vivo efficacy in multiple pre-clinical DLBCL models.
Ten of 12 germinal center B-cell (GCB) and two of four activated B-cell (ABC) DLBCL cell lines show significant growth inhibition in-vitro with BCL6 PROTAC TM treatment, demonstrating a critical dependence on BCL6. This array of sensitivity across genetically variable cell lines suggests that BCL6-dependence is not just associated with BCL6-mutated DLBCLs. A more advanced BCL6 PROTAC TM, ARVN-71228, achieves >95% BCL6 D max in-vitro at a DC 50 of <1 nM in the OCI-Ly1 model following 24 hr treatment, degrading BCL6 equally well in the nuclear, chromatin-bound and cytosolic cell fractions. BCL6 degradation is associated with dose-dependent G1 cell cycle arrest and elevated apoptosis that increases over time (24 vs 72 hours). In head-to-head BCL6 degradation and growth inhibition studies using OCI-Ly1, the ARVN-71228 BCL6 PROTAC TM demonstrates superior activity compared to recently published BCL6-targeted degraders/inhibitors and heterobifunctional molecules.
Importantly, medicinal chemistry efforts have resulted in the successful development of orally bioavailable BCL6 PROTAC TM degraders for in-vivo dosing. Time-course studies show >95% BCL6 loss within four hours which is maintained at 8-, 16- and 24-hours. Genes repressed by BCL6 such as BLIMP1 and PTPN6 are derepressed and show increased protein levels 24 hours post-dose. ARVN-71228 achieves regressions in the GCB OCI-Ly1 CDX model. Future studies plan to look at rational drug combinations with BCL6 PROTAC TM degraders to find collaborative or synergistic pathways to target, especially in the HR-DLBCL subtypes where there is a high unmet medical need.
Gough: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sherman: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. DeCarr: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Eaton: Arvinas: Current Employment, Current equity holder in publicly-traded company. Milanovic: Arvinas: Current Employment, Current equity holder in publicly-traded company. Bookbinder: Arvinas: Current Employment, Current equity holder in publicly-traded company. Pizzano: Arvinas: Current Employment, Current equity holder in publicly-traded company. Altieri: Arvinas: Current Employment, Current equity holder in publicly-traded company. Corradi: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Xiao: Arvinas: Current Employment, Current equity holder in publicly-traded company. Gallego: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Soto: Arvinas: Current Employment, Current equity holder in publicly-traded company. Lingamaneni: Arvinas: Current Employment, Current equity holder in publicly-traded company. Chen: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Zhang: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Wang: Arvinas: Current Employment, Current equity holder in publicly-traded company. Dong: Arvinas: Current Employment, Current equity holder in publicly-traded company. Chirnomas: Arvinas: Current Employment, Current equity holder in publicly-traded company. Berlin: Arvinas: Current Employment, Current equity holder in publicly-traded company. Hornberger: Arvinas: Current Employment, Current equity holder in publicly-traded company. Snyder: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Taylor: Arvinas: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.
