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:
“𝘔𝘰𝘥𝘶𝘭𝘢𝘳 𝘗𝘙𝘖𝘛𝘈𝘊/𝘐𝘔𝘪𝘋 𝘉𝘪𝘧𝘶𝘯𝘤𝘵𝘪𝘰𝘯𝘢𝘭 𝘔𝘰𝘭𝘦𝘤𝘶𝘭𝘦 𝘋𝘦𝘴𝘪𝘨𝘯 𝘧𝘰𝘳 𝘵𝘩𝘦 𝘋𝘦𝘨𝘳𝘢𝘥𝘢𝘵𝘪𝘰𝘯 𝘰𝘧 𝘚𝘺𝘯𝘦𝘳𝘨𝘪𝘴𝘵𝘪𝘤 𝘛𝘢𝘳𝘨𝘦𝘵𝘴 𝘪𝘯 𝘵𝘩𝘦 𝘛𝘳𝘦𝘢𝘵𝘮𝘦𝘯𝘵 𝘰𝘧 𝘓𝘺𝘮𝘱𝘩𝘰𝘮𝘢”
Using these dual degraders authors target therapeutically synergistic combination:
BC6: Dual BCL6/IKZF1/3 Degrader
✅ Designed using BI-3812 as BCL6 ligand
✅ Subnanomolar DC₅₀ for BCL6 (0.08–1.04 nM) and low-nanomolar DC₅₀ for IKZF1/3 across multiple DLBCL lines
✅ Proteomics revealed selective degradation of BCL6 and IKZF1/3
✅ Oral bioavailability in mice (Cmax 373.8 ng/mL; AUC₀–t 3359.5 ng·h/mL).
✅ Antiproliferative IC₅₀ of 0.46–35.68 nM, outperforming PROTACs, IMiDs, and non-IMiD PROTACs
✅ In vivo OCI-Ly1 xenograft: PO admin. 25–50 mg/kg yielded 63.6–72.2% tumor growth inhibition with no body-weight loss or histopathological toxicity.
BT6: Dual BTK/UKZF1/3 Degrader
✅ Designed using BTK inhibitor (from WO2015/084998A1)
✅ Good PK profile: Cmax 5662.7 ng/mL
✅ 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:
“𝘙𝘢𝘵𝘪𝘰𝘯𝘢𝘭 𝘋𝘦𝘴𝘪𝘨𝘯 𝘰𝘧 𝘋𝘶𝘢𝘭 𝘋𝘦𝘨𝘳𝘢𝘥𝘦𝘳𝘴 𝘣𝘺 𝘐𝘯𝘤𝘰𝘳𝘱𝘰𝘳𝘢𝘵𝘪𝘯𝘨 𝘔𝘰𝘭𝘦𝘤𝘶𝘭𝘢𝘳 𝘎𝘭𝘶𝘦 𝘚𝘵𝘳𝘶𝘤𝘵𝘶𝘳𝘢𝘭 𝘍𝘦𝘢𝘵𝘶𝘳𝘦𝘴 𝘪𝘯𝘵𝘰 𝘗𝘙𝘖𝘛𝘈𝘊 𝘋𝘦𝘨𝘳𝘢𝘥𝘦𝘳𝘴”
BWA-6047 potency
✅ Remarkably potent inhibitory activity against AR-dependent prostate cancer cells:
22Rv1: IC50 = 1.1 nM
VCaP: IC50 = 1.5 nM
LNCaP: IC50 = 2.8 nM
✅ Despite low bioavailability (F = 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.