Is It PROTAC or Molecular Glue? … It Is Both!
Researchers often steer the design of CRBN-based PROTACs to achieve selective degradation of a single target while suppressing degradation of CRBN neo-substrates.
Two different research groups published independently two publications where they approached this differently. By intentional design they developed dual degraders by combining the principles of PROTACs and molecular glue degraders.
The first work was published in JACS:
“๐๐ฐ๐ฅ๐ถ๐ญ๐ข๐ณ ๐๐๐๐๐๐/๐๐๐ช๐ ๐๐ช๐ง๐ถ๐ฏ๐ค๐ต๐ช๐ฐ๐ฏ๐ข๐ญ ๐๐ฐ๐ญ๐ฆ๐ค๐ถ๐ญ๐ฆ ๐๐ฆ๐ด๐ช๐จ๐ฏ ๐ง๐ฐ๐ณ ๐ต๐ฉ๐ฆ ๐๐ฆ๐จ๐ณ๐ข๐ฅ๐ข๐ต๐ช๐ฐ๐ฏ ๐ฐ๐ง ๐๐บ๐ฏ๐ฆ๐ณ๐จ๐ช๐ด๐ต๐ช๐ค ๐๐ข๐ณ๐จ๐ฆ๐ต๐ด ๐ช๐ฏ ๐ต๐ฉ๐ฆ ๐๐ณ๐ฆ๐ข๐ต๐ฎ๐ฆ๐ฏ๐ต ๐ฐ๐ง ๐๐บ๐ฎ๐ฑ๐ฉ๐ฐ๐ฎ๐ข”
Using these dual degraders authors target therapeutically synergistic combination:
BC6: Dual BCL6/IKZF1/3 Degrader
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Designed using BI-3812 as BCL6 ligand
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Subnanomolar DCโ
โ for BCL6 (0.08โ1.04 nM) and low-nanomolar DCโ
โ for IKZF1/3 across multiple DLBCL lines
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Proteomics revealed selective degradation of BCL6 and IKZF1/3
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Oral bioavailability in mice (Cmax 373.8 ng/mL; AUCโโt 3359.5 ngยทh/mL).
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Antiproliferative ICโ
โ of 0.46โ35.68 nM, outperforming PROTACs, IMiDs, and non-IMiD PROTACs
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In vivo OCI-Ly1 xenograft: PO admin. 25โ50 mg/kg yielded 63.6โ72.2% tumor growth inhibition with no body-weight loss or histopathological toxicity.
BT6: Dual BTK/UKZF1/3 Degrader
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Designed using BTK inhibitor (from WO2015/084998A1)
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Good PK profile: Cmax 5662.7 ng/mL
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Superior in vitro/in vivo efficacy versus ibrutinib and NX-2127, and no observable toxicity.
Link to full original publication: //https://lnkd.in/e6ujssTB
The second publication descibes the dual degrader (PROTAC + Mol. glue) BWA-6047 targeting androgen receptor (AR) and its splice variant (AR-V7) and GSPT1:
“๐๐ข๐ต๐ช๐ฐ๐ฏ๐ข๐ญ ๐๐ฆ๐ด๐ช๐จ๐ฏ ๐ฐ๐ง ๐๐ถ๐ข๐ญ ๐๐ฆ๐จ๐ณ๐ข๐ฅ๐ฆ๐ณ๐ด ๐ฃ๐บ ๐๐ฏ๐ค๐ฐ๐ณ๐ฑ๐ฐ๐ณ๐ข๐ต๐ช๐ฏ๐จ ๐๐ฐ๐ญ๐ฆ๐ค๐ถ๐ญ๐ข๐ณ ๐๐ญ๐ถ๐ฆ ๐๐ต๐ณ๐ถ๐ค๐ต๐ถ๐ณ๐ข๐ญ ๐๐ฆ๐ข๐ต๐ถ๐ณ๐ฆ๐ด ๐ช๐ฏ๐ต๐ฐ ๐๐๐๐๐๐ ๐๐ฆ๐จ๐ณ๐ข๐ฅ๐ฆ๐ณ๐ด”
BWA-6047 potency
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Remarkably potent inhibitory activity against AR-dependent prostate cancer cells:
22Rv1: IC50ย = 1.1 nM
VCaP: IC50ย = 1.5 nM
LNCaP: IC50ย = 2.8 nM
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Despite low bioavailability (Fย = 11.2%) it achieved 60% tumor growth inhibition and no apparent toxicity (LNCaP castrated xenograft tumor model)
Link to full original publication: : https://lnkd.in/e3z-kcNn
Share your perspective
Have you seen any other PROTAC+molecular glue hybrid degraders, or do you have ideas for future synergistic target combinations?
Which approach do you think is the future: dual/poly degraders in one molecule, or cocktail of multiple single-target degraders given together?
Leave you comment under my LinkedIn post here.