Cell｜双价分子胶连接p300/CBP与BCL6，激活淋巴瘤细胞死亡程序
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TL;DR - A Stanford/MD Anderson-led Cell paper reports TCIP3, a bivalent molecular glue that forces a cooperative ternary complex between the acetyltransferases p300/CBP and the oncogenic repressor BCL6, converting BCL6 from a survival factor into a trigger for cell-cycle arrest and apoptosis in DLBCL. It matters because it extends chemically induced proximity beyond degradation into targeted transcriptional/epigenetic reprogramming.
- Design: BCL6 BTB-domain ligands were linked to p300/CBP bromodomain binders; a hit (MNN-02-155) activated a BCL6 reporter, and crystallography showed a new p300–BCL6 interface stabilized by opportunistic H-bonds and shape complementarity, adding <3% of domain surface area with no major conformational change — mutating interface residues reduced cooperativity.
- Potency and gain-of-function: linker rigidification plus docking/MD yielded TCIP3, with IC50 0.80 nM in SUDHL5 cells, stronger than inhibiting or degrading either protein alone; NanoBRET indicated only a small fraction of BCL6 need be engaged, activity persisted with a single catalytic EP300/CREBBP allele, and toxicity tracked BCL6 levels (weak in BCL6-low leukemia cells, primary fibroblasts, tonsillar lymphocytes).
- Chromatin/transcription effects: ChIP-seq showed ~4-fold higher p300 signal near BCL6 sites (~80% overlap), with no global H3K27ac/H2BK20ac change; BCL6 targets such as ARID3B and CDKN1B gained acetylation while germinal-center/proliferation super-enhancers (MEF2B, IRF8, SPIB, BCL6) lost it, and c-MYC fell while p27 and PUMA rose, causing G1 arrest and apoptosis.
- In vivo: ~3.33 h half-life after single IP dosing; dose-dependent depletion of BCL6-high germinal center B cells with total B cells largely unchanged; 5 mg/kg twice daily gave complete or near-complete SUDHL5 xenograft clearance by day 11 without organ damage or cytokine inflammation, though two mice lost weight, so dose/safety window needs optimization.
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Cell｜双价分子胶连接p300/CBP与BCL6，激活淋巴瘤细胞死亡程序
TL;DR - A Stanford/MD Anderson-led Cell paper reports TCIP3, a bivalent molecular glue that forces a cooperative ternary complex between the acetyltransferases p300/CBP and the oncogenic repressor BCL6, converting BCL6 from a survival factor into a trigger for cell-cycle arrest and apoptosis in DLBCL. It matters because it extends chemically induced proximity beyond degradation into targeted transcriptional/epigenetic reprogramming.
- Design: BCL6 BTB-domain ligands were linked to p300/CBP bromodomain binders; a hit (MNN-02-155) activated a BCL6 reporter, and crystallography showed a new p300–BCL6 interface stabilized by opportunistic H-bonds and shape complementarity, adding <3% of domain surface area with no major conformational change — mutating interface residues reduced cooperativity.
- Potency and gain-of-function: linker rigidification plus docking/MD yielded TCIP3, with IC50 0.80 nM in SUDHL5 cells, stronger than inhibiting or degrading either protein alone; NanoBRET indicated only a small fraction of BCL6 need be engaged, activity persisted with a single catalytic EP300/CREBBP allele, and toxicity tracked BCL6 levels (weak in BCL6-low leukemia cells, primary fibroblasts, tonsillar lymphocytes).
- Chromatin/transcription effects: ChIP-seq showed ~4-fold higher p300 signal near BCL6 sites (~80% overlap), with no global H3K27ac/H2BK20ac change; BCL6 targets such as ARID3B and CDKN1B gained acetylation while germinal-center/proliferation super-enhancers (MEF2B, IRF8, SPIB, BCL6) lost it, and c-MYC fell while p27 and PUMA rose, causing G1 arrest and apoptosis.
- In vivo: ~3.33 h half-life after single IP dosing; dose-dependent depletion of BCL6-high germinal center B cells with total B cells largely unchanged; 5 mg/kg twice daily gave complete or near-complete SUDHL5 xenograft clearance by day 11 without organ damage or cytokine inflammation, though two mice lost weight, so dose/safety window needs optimization.