First In Class Orally Bioavailable Betbrd Degraders

Background: Inhibition of Bromodomain and extra-terminal (BET) family proteins by small molecules is actively being pursued as a therapeutic strategy in the clinics. Targeted protein degradation is an emerging therapeutic modality that has shown initial promise in the clinic. BET protein degradation has inherent advantages over inhibition viz. expansion of indication scope and amenability to intermittent dosing schedules. While many BET degraders have been disclosed earlier, inferior pharmacokinetic properties limit their further development. Methods and Results: We have designed and synthesized various hetero bi-functional molecules by conjugating novel and selective BET BRD ligands with VHL or CRBN ligands. This exercise led to the identification of several potent and selective BRD4 protein degraders with activity in a wide range of hematological and solid tumor cell lines. We have profiled one of the lead compounds extensively in vitro to gain insights on the mechanism of action. The lead compound showed lasting effect on BET protein abundance post compound washout while leading to apoptosis. This compound has favorable IV PK profile in rodents had has clean CYP and hERG profiles. Additionally, the lead compound exhibited significant tumor growth inhibition in MV4-11 xenograft model when dosed via i.v. route. Both QD and Q48h dosing regimens were well tolerated and produced efficacy in mouse models. Further SAR in the linker portion resulted in compounds with lower iv clearance and oral bioavailability either as prodrugs or as such. The proteomics study revealed a high selectivity towards BET proteins for the lead compound. Conclusions: Potent and selective BET protein degraders were identified by conjugating novel BET BRD ligands with both VHL and CRBN ligands. Optimization of these first generation BET degraders led to improved metabolic stability, translating into low iv clearance in rodents. Further evaluation of these compounds as prodrugs resulted in good oral exposures. Lead compounds from both the series have low iv clearance and are orally bioavailable in a simple formulation. We believe these compounds serve as valuable tools to fully understand the clinical scope of BET degraders. Citation Format: Chandrasekhar Abbineni, Mahaboobi Jaleel, Subhendu Mukherjee, Sivapriya Marappan, Nirbhay Kumar Tiwari, DS Samiulla, AB Aravind, Naveen R Kumar, Indu Bansal, Raghurami B Reddy, NVM Rao Bandaru, Akhila Srinivas, Janith Mary Maben, Suraj Tgore, Avainash Kumar, Rakesh P. Nankar, Chandranath D. Naik, Thomas Antony, Kavitha Nellore, Sanjeev Giri, Girish Daginakatte, Shekar Chelur, Olli Tormakangas, Gerd Wohlfahrt, Mari Bjorkman, Elina Mattila, Laura Ravanti, Anu Moilanen, Murali Ramachandra, Susanta Samajdar. First in class orally bioavailable BETBRD degraders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1754.