Abstract 3729: Discovery of orally bioavailable SMARCA2/4 dual degraders for treatment of acute myeloid leukemia

Background: The BAF (SWI/SNF) chromatin remodeling complex comprises of two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1), that affect the mobilization and positioning of nucleosomes on DNA and thereby regulates important cellular functions including transcription, DNA recombination, DNA repair and chromosome decatenation during mitosis. SMARCA4 is frequently overexpressed in several types of cancers. Overexpression has been linked to increased proliferation and survival, as well as aggressive tumors and poor prognosis. SMARCA4 knockdown in these tumors lead to inhibition of proliferation and increased sensitivity to known chemotherapeutic agents, supporting the validity of targeting SMARCA4. Genetic silencing studies have established that the oncogenic activity of tumors lacking SMARCA4 is primarily driven by SMARCA2-containing residual SWI/SNF complex, suggesting the importance of dual inhibition of SMARCA2 and SMARCA4. While SMARCA4 is known to play a vital role in maintaining the oncogenic transcription program and driving proliferation in leukemia, the impact of dual SMARCA2 and SMARCA4 inhibition/degradation in acute myeloid leukemia (AML) is largely unexplored. Methods and Results: As part of the initial design plan, selective SMARCA2/4 Bromodomain inhibitors and specific ligands of several E3 ligases were chosen to arrive at different degrader designs. A choice of linkers and different exit vectors were considered to construct a variety of hetero bifunctional molecules. Our proprietary ternary complex modeling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders) helped in prioritizing the designs. Short listed compounds were synthesized and profiled in multiple cellular assays to understand their degradation potential. Several compounds that degrade SMARCA2, SMARCA4 & PBRM1 with pico molar DC50 were identified. These compounds have shown very potent anti-proliferative activity in both SMARCA2/4 proficient (MV-4-11, VCaP etc) and SMARCA4 mutant cell lines (SK-MEL-5 & RERF-LC-A1 etc). Further, potent compounds were optimized for their pharmacokinetic properties. Multiple lead compounds with low IV clearance and good oral bioavailability in rodents were identified. Advanced lead compounds are currently being evaluated in rodent tolerability and PK-PD experiments to select doses for the efficacy study. Conclusions: Highly potent degraders of SMARCA2, SMARCA4 & PBRM1 were identified by conjugating selective SMARCA2/4 Bromodom