NOVEL SALL4 DEGRADER FOR CANCER TREATMENT

Abstract

SALL4 is essential for the survival of approximately 30% of solid tumors and leukemia. It has two isoforms: the longer isoform SALL4A and the short isoform SALL4B. The reported immunomodulatory imide drugs (IMiDs) can only degrade SALL4A, not SALL4B, and have no therapeutic effects in SALL4-mediated cancer cells. Further studies suggested that SALL4B is the dominant oncogenic isoform. In this work, a high-throughput screening of 50,000 small molecules was performed to identify SALL4B degraders for cancer treatment. The screen comprises of thermal shift assay, SALL4B luciferase reporter cellular assay, and cell viability assay. A new cereblon modulator, QE, was discovered, which effectively depleted SALL4B via proteasomal degradation. QE exhibited significant anti-cancer effects, inhibiting cancer cell viability in culture and in vivo tumor growth by 70% in the HCC xenograft mouse model. The discovery of QE offers an opportunity to develop this lead candidate further as a drug toward human trials