Identification of a small molecule degrader targeting SALL4 oncogene

Recent studies have shown that immunomodulatory imide drugs (IMiDs) could degrade SALL4 through a proteasome-dependent mechanism. Intriguingly, we found that IMiDs do not affect SALL4-positive cancer cell survival. Further studies revealed IMiDs could only degrade SALL4A, one of the SALL4 isoforms. This suggests that SALL4B, the isoform not affected by IMiDs, might be essential or compensating SALL4A in supporting cancer cell survival. Indeed, knocking downSALL4B increased apoptosis and inhibited cancer cell growth, similar to knocking down bothSALL4A and B. Moreover, SALL4B gain-of-function alone led to liver tumor formation in mice. Through high-throughput screening, we discovered a new non-IMiD degrader that targetsSALL4A and SALL4B via proteasomal degradation, showing potent anti-cancer activity by inhibiting cancer cell proliferation in culture and in vivo tumor growth by 70%. Gene expression profiling via RNA-sequencing identified a shared drug and SALL4B knock down gene signature in hepatocellular carcinoma (HCC) cells, including pathways involved in DNA damage response and DNA replication. Our findings highlight the importance of understanding drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.