A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα
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This paper invents PI3Kα degraders with α/β selectivity tunable based on linker composition along with a structural rationale proposed. PI3Ka, a key protein frequently mutated in various cancers and a crucial player in cellular growth regulation. The researchers address the challenge of developing effective treatments against PI3Ka, which has been hampered by the lack of isoform-specific inhibitors and the associated adverse effects caused by pan-PI3K inhibition. This work presents a novel strategy utilizing targeted protein degradation, specifically PROTACs, to overcome these limitations.
The paper's central argument hinges on the creation of a high-affinity pan-PI3K binding module that serves as the cornerstone for selective PI3Ka degradation. This module, derived from the potent pan-PI3K inhibitor PQR514, exhibits excellent selectivity for class I PI3Ks, thus laying the foundation for a targeted approach. The researchers strategically incorporate this module into a cereblon-targeted (CRBN) PROTAC, a small molecule that utilizes the ubiquitin-proteasome system (UPS) to selectively degrade target proteins. The paper meticulously describes the design and optimization of the PROTACs, highlighting the importance of linker length and hydrophobicity in achieving potent degradation. The authors systematically investigate the impact of varying linker lengths, ranging from 11 to 17 atoms, on both in vitro binding affinity and in-cell degradation activity. This approach reveals a clear correlation between linker length and degradation efficiency, with 14-16 atom linkers demonstrating optimal degradation efficacy. Additionally, the researchers emphasize the crucial role of linker hydrophobicity, illustrating that hydrophilic linkers significantly diminish the degradation potential.
To validate the degradation mechanism, the researchers employ various strategies, including chemical rescue experiments and saturation of CRBN-binding sites. These studies conclusively establish the involvement of the CRBN E3 ligase complex and the UPS in p110a degradation, confirming that the degradation is not merely an inhibition of protein activity but rather a targeted removal of the protein itself. Moreover, the authors demonstrate that WJ112-14, the optimized PROTAC, exhibits a remarkable level of selectivity, degrading p110a while sparing p110b, a closely related isoform. This selectivity is further supported by extensive proteomics analyses using both parallel reaction monitoring (PRM) and tandem mass tag (TMT) approaches, providing comprehensive data on protein levels across multiple cell lines. The results consistently show that WJ112-14 demonstrates significantly higher degradation efficiency for p110a than p110b, even at lower concentrations. The paper then delves into the mechanistic underpinnings of the observed selectivity. Through computational modelling, the researchers propose that the linker of WJ213-14, a structurally similar PROTAC but with a less selective degradation profile, interacts with a specific residue (D856 in mouse) in the p110b isoform, leading to its degradation. In contrast, WJ112-14 lacks this specific interaction, resulting in its high selectivity for p110a degradation.
The paper concludes by comparing WJ112-14's performance with existing p110a inhibitors, including taselisib and a previously reported CRBN-based degrader (Li_2018_D). WJ112-14 demonstrates superior degradation efficacy, both in terms of speed and effectiveness, in various cell lines including those resistant to taselisib-mediated degradation. This research holds significant implications for cancer therapeutics. The development of WJ112-14, a highly potent and selective PI3Ka degrader, offers a promising avenue for treating PI3Ka-mutated cancers. The study emphasizes the potential of PROTACs as a powerful tool for targeted protein degradation, offering a distinct advantage over traditional inhibitors. However, the authors acknowledge the need for further research to explore the broader implications of this technology. Specifically, they highlight the importance of exploring the off-target effects and potential toxicities associated with WJ112-14, as well as investigating its efficacy in vivo.
Despite these open questions, this paper represents a significant advancement in the field of targeted protein degradation. It showcases the potential of PROTACs to address the challenges of drug resistance and side effects associated with conventional inhibitors, opening new avenues for developing effective and selective therapies for a range of diseases, particularly cancer.
https://pubs.rsc.org/en/content/articlelanding/2024/SC/D3SC04629J
