Dual-ligase PROTACs: a novel approach for enhancing TPD. By recruiting two distinct E3 ligases within a single molecule, we amplify degradation efficacy & potentially mitigate resistance occurrence. Great collabo with the Ciulli lab & friends at Promega. pubs.acs.org/doi/10.1021/... - ThreadSky

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georgwinter.bsky.social • 90 days ago

Dual-ligase PROTACs: a novel approach for enhancing TPD. By recruiting two distinct E3 ligases within a single molecule, we amplify degradation efficacy & potentially mitigate resistance occurrence. Great collabo with the Ciulli lab & friends at Promega.
https://pubs.acs.org/doi/10.1021/jacs.4c11556

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quinnsievers.bsky.social•90 days ago

Super cool! Re: mitigating resistance, I’ve always found it curious that while CRBN seems to be readily lost in cell lines via CRISPR screens we have not seen LOF mutations in CRBN with lenalidomide in the context of myeloma. There are anecdotal cases and maybe some evidence for reduced expression.

quinnsievers.bsky.social•90 days ago

Will be interesting to see if that changes with CRBN-based PROTACS being used in the clinic in other disease contexts.

georgwinter.bsky.social•90 days ago

this is a great point, Quinn! I'd argue that IMiDs are also efficacious through non cancer cell-autonomous mechanisms, thereby reducing selective pressure.

quinnsievers.bsky.social•90 days ago

Oh interesting I hadn’t thought of that! You mean by altering T cell function through degradation of Ikaros and Aiolos?

georgwinter.bsky.social•90 days ago

exactly! T cell ans NK cell activation in addition to the direct targeting of the MM vulnerability.

pedalheadphx.bsky.social•89 days ago

Most tumor inactivations I’ve seen that are convincing are after pomalidomide, very few clonal after lenalidomide beyond shift from 3 copies in hyperdipoid myeloma to 2 copies. Do wonder what we will see with next generation versions like iber and mezi, but agree with the hypothesis.

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