Modulation of BAZ2 Proteins as a Potential Therapeutic Strategy in Cancer and Neurological Disorders

The complex landscape behind protein homeostasis involves a highly sophisticated system devoted to maintaining cellular balance and preventing dysfunction. In this context, the cellular machinery acts as a quality control mechanism, rapidly identifying and eliminating proteins that could impair normal cell functioning. Currently, such a mechanism is strategically employed by researchers to promote the degradation of proteins of interest (POI), acting as relevant players in pathological conditions. The cellular degradation system is " hijacked " toward target elimination by exploiting PROteolysis Targeting Chimera (PROTAC) technology. This innovative approach allows protein degradation by fostering interactions between an E3 ubiquitin ligase and a POI, effectively directing the ubiquitin-proteasome system to eliminate the target protein. In this study, we harness the potential of the PROTAC technology to promote the degradation of BAZ2A protein while providing insights into the complex mechanism relating this target to prostate cancer. Recent studies have highlighted BAZ2A’s role in late-stage prostate cancer, prompting us to explore its potential as a therapeutic target. Therefore, we first interfered with BAZ2A pathological functions by hampering through a competitive inhibitor its ability to recognise acetylated lysines (Kac) at the histone tails. Although Kac recognition represents a key BAZ2A function, simple inhibition did not produce any antiproliferative effect in prostate cancer cell lines. On the other hand, BAZ2A ablation through RNA interference displayed promising results by slowing the proliferation rate and strongly affecting the expression of genes related to BAZ2A dysregulation in cancer. Thus, we decided to exploit PROTAC technology to replicate the beneficial effect observed upon BAZ2A ablation through silencing RNAs. BAZ2A binding PROTAC molecules were designed based on available BAZ2A structures. The synthesis of eleven BAZ2A degraders was accomplished, categorizing PROTACs according to their capability to recruit CRBN or VHL E3 ligases. Preliminary experiments revealed that VHL-based degraders featuring longer linkers promoted BAZ2A degradation, confirming the PROTAC potential in successfully mediating POI degradation. Attempts at X-ray structure determination of ternary complexes of BAZ2A/B, a PROTAC molecule and VHL-EloB/C resulted in structures of binary complexes at best and will form the basis of future structural efforts towards the same targets. Here, we report an extensive study on the role of BAZ2A in tumorigenic conditions, proposing targeted protein degradation as a promising strategy to counteract aggressive prostate cancer. Notably, BAZ2A ablation was achieved by successfully designing and synthesizing PROTAC degraders. Future work will confirm the therapeutic potential of this strategy, including the possibility of targeting BAZ2B, a related protein implicated in the ageing process.