Abstract 1250: Antitumor activities of CD161, a structurally novel and orally bioavailable BET inhibitor, in leukemia and triple negative breast cancer cells in vitro and in vivo

Abstract

Abstract Bromodomain and extraterminal (BET) proteins, such as bromodomain-containing protein 2 (BRD2), BRD3 and BRD4, bind lysine acetylated proteins and regulate gene transcription. Several BET inhibitors are currently under clinical development for hematological malignancies and solid tumors. We have recently developed a novel class of BET inhibitor, CD161, which binds the bromodomain 1 (BD1) and BD2 domains of BRD2, BRD3, BRD4 and BRDT with Ki less than 10 nM. Co-crystal structure of CD161 and BRD4 BD2 at 2.5 Å resolution confirmed that the docked CD161 occupies the acetyl-lysine binding pocket of BD2. CD161 has >1000-fold selectivity over other bromodomain containing proteins including CREBBP, ATAD2B, TRIM24 and ASH1L. In human leukemia cell lines MV4-11 and MOLM-13, CD161 strongly inhibits cell growth and induces apoptosis, with IC50s <100 nM. Furthermore, CD161 exerts potent growth-inhibitory activities in a panel of breast cancer cell lines representative of triple-negative breast cancer (TNBC), with IC50s in the sub micromolar range. At 20-50 mg/kg daily oral dosing for 2 weeks, CD161 significantly inhibited the growth of MV4-11 and MDA-MB-231 tumors (TGI: 55-80%) in mouse xenograft models and had no significant effect on body weights. Pharmacokinetics studies show that CD161 has a T1/2 of 2-3 hours and oral bioavailability (F%) of 93% in male Sprague−Dawley rats. Transcriptional profiling revealed that CD161 causes broad transcriptional changes in TNBC cell lines. Our preliminary results suggest the therapeutic potential of CD161 in human leukemia and TNBC. Citation Format: Longchuan Bai, Yujun Zhao, Liu Liu, Chao-Yie Yang, Donna McEachern, Jeanne Stuckey, Jennifer Meagher, Bo Wen, Duxin Sun, Shaomeng Wang. Antitumor activities of CD161, a structurally novel and orally bioavailable BET inhibitor, in leukemia and triple negative breast cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1250.