Abstract 5083: A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia

The bromodomain and extra-terminal domain (BET-BRD) family of lysine acetylation readers comprises BRD2, BRD3, BRD4, and BRDT that contain two conserved N-terminal bromodomains (BD1 and BD2) and a long C-terminal region containing the extraterminal (ET) protein-protein interaction domain. These proteins have key roles in the assembly of transcriptional regulatory complexes containing RNA polymerase II. BET-BRDs are new therapeutic targets for cancer treatment and several small-molecule BET-BRD inhibitors are currently in clinical development for a diverse set of cancers including leukemia. Based on the proteolysis targeting chimera (PROTAC) concept, we have developed novel and highly potent BET degraders, ZBC246 and ZBC260, with exceptional selectivity based upon a new class of BET inhibitor, ZBC11. ZBC260 effectively degrades all BET-BRD proteins at concentrations as low as 30 pM within a few hours of treatment in the RS4;11 leukemia cell line and achieves IC50 values of 50 pM in inhibition of RS4;11 cell growth. ZBC260 was tested in a panel of 10 acute leukemia cell lines generating IC50s ranging from 20 pM to 1 nM in 4-days cell growth inhibition assays. In contrast to the cytostatic effect observed with BET-BRD inhibition, degradation of BET-BRDs by ZBC246 and ZBC260 induced robust apoptosis demonstrating a differential biology between BET-BRD inhibitors and BET-BRD degraders. Significantly, ZBC260 induces rapid regression of RS4;11 xenograft tumors without overt signs of toxicity in mice. More importantly, treatment of leukemia cells obtained from 10 patients with ZBC260 demonstrated efficient degradation of BET-BRDs within 5 h at 0.3 nM, while treatment with the inhibitor (300 nM) induced up-regulation of BET-BRDs. Treatment of patients’ peripheral blasts with ZBC260 at 1 to 10 nM induced remarkable levels of apoptosis within 24 h, even in relapsed and refractory patient samples. In conclusion, ZBC260 represents a highly potent and efficacious BET-BRD degrader undergoing extensive preclinical evaluation for the treatment of acute leukemias. Citation Format: Ester Fernandez-Salas, Zhuo Chen, Mei Lin, Bing Zhou, Donna McEachern, Sally Przybranowski, Karson Kump, Luke F. Peterson, Malathi Kandarpa, Jiantao Hu, Fuming Xu, Liu Liu, Longchuan Bai, Bo Wen, Duxin Sun, Moshe Talpaz, Shaomeng Wang. A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2017-5083