PMV6-PEG4-BI2536 is an RIPTAC-like bifunctional molecule that promotes the formation of the p53 Y 220C -PLK1 ternary complex ( EC 50 = 1.4 μM). PMV6-PEG4-BI2536 causes PLK1 mislocalization and inhibits PLK1 activity, inducing G2/M phase arrest and apoptosis in p53 Y 220C -mutant cells, while sparing cells with wild-type TP53. PMV6-PEG4-BI2536 can be used in research on uterine, gastric, pancreatic, prostate, and breast cancers harboring the p53 Y 220C mutation. PMV6-PEG4-BI2536 is composed of PMV6 (a p53 Y 220C mutant-binding ligand), PEG4 (a linker), and BI2536 (a PLK inhibitor) [1].
In Vitro, PMV6-PEG4-BI2536 (compound p53-01) (1 nM-10 μM; 24 h) induces an increase in luminescence signals in 293T cells co-transfected with NLS-LgBiT-p53-Y220C and mEGFP-PLK1-SmBiT, indicating the promotion of ternary complex formation between p53-Y220C and PLK1 (EC50 = 1.4 μM)[1]. PMV6-PEG4-BI2536 (62.5 nM-2 μM; 8 days) selectively inhibits the proliferation of mutant cells in a co-culture system of TP53Y220C-mutant 293T cells and wild-type 293T cells (EC50 = 443 nM)[1]. PMV6-PEG4-BI2536 (1 nM-1 μM; 8 days) dose not affect the proliferative capacity of P53-R273H (FL)-mutant 293T cells[1]. PMV6-PEG4-BI2536 (7.5 μM-1.5 μM; 5 days) significantly inhibits the proliferation of TP53Y220C-mutant 293T cells [1]. PMV6-PEG4-BI2536 (62.5 nM-1 μM; 7 days) dose not affect the proliferative capacity of P53-R273H (FL)-mutant CALU-1 cells or wild-type CALU-1 cells [1]. PMV6-PEG4-BI2536 (1.5 μM; 1 day) upregulates Caspase 3/7 activity and induces apoptosis in TP53Y220C-mutant 293T cells[1]. PMV6-PEG4-BI2536 (0.75-1.5 μM; 1 day) increases the proportion of early and late apoptotic cells in TP53Y220C-mutant 293T cells[1]. PMV6-PEG4-BI2536 (0.375-1.5 μM; 1 day) induces G2/M phase arrest in TP53Y220C-mutant 293T cells synchronized with Palbociclib [1]. PMV6-PEG4-BI2536 (1.5 μM; 8.5 h) inhibits PLK1 activity in TP53Y220C-mutant 293T cells synchronized via double-thymidine block[1]. PMV6-PEG4-BI2536 (4 days) significantly inhibits the proliferation of most Y220C+ cell lines (MFE319 (IC50 = 1268.3102 nM), NUGC3 (IC50 = 1713.0956 nM), MFE296 (IC50 = 4320.9284 nM), BxPC-3 (IC50 = 8251.9582 nM)) and the Y220C- cell line MCF7 (IC50 = 1268.3102 nM). PMV6-PEG4-BI2536 has no significant effect on the proliferation of the Y220C+ cell line Huh7 (IC50 = 20000 nM) or most Y220C- cell lines (LNCaP (IC50 = 14113.1353 nM), DU145 (IC50 = 20000 nM), HepG2 (IC50 = 20000 nM)).[1]. PMV6-PEG4-BI2536 (0.16-1.25 μM; 9 days) shows no significant cytotoxic effect on TP53-knockout MFE319 cells in a co-culture system with wild-type MFE319 cells[1]. PMV6-PEG4-BI2536 (62.5-250 nM; 3 weeks) reduces the proportion of TP53Y220C-mutated 293T cells[1].
References:
[1]. Sadagopan A, et al. Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs. Nat Chem Biol. 2026 May;22(5):783-792. doi: 10.1038/s41589-025-02051-7. Epub 2025 Nov 3. Erratum in: Nat Chem Biol. 2026 May;22(5):840.
In Vitro, PMV6-PEG4-BI2536 (compound p53-01) (1 nM-10 μM; 24 h) induces an increase in luminescence signals in 293T cells co-transfected with NLS-LgBiT-p53-Y220C and mEGFP-PLK1-SmBiT, indicating the promotion of ternary complex formation between p53-Y220C and PLK1 (EC50 = 1.4 μM)[1]. PMV6-PEG4-BI2536 (62.5 nM-2 μM; 8 days) selectively inhibits the proliferation of mutant cells in a co-culture system of TP53Y220C-mutant 293T cells and wild-type 293T cells (EC50 = 443 nM)[1]. PMV6-PEG4-BI2536 (1 nM-1 μM; 8 days) dose not affect the proliferative capacity of P53-R273H (FL)-mutant 293T cells[1]. PMV6-PEG4-BI2536 (7.5 μM-1.5 μM; 5 days) significantly inhibits the proliferation of TP53Y220C-mutant 293T cells [1]. PMV6-PEG4-BI2536 (62.5 nM-1 μM; 7 days) dose not affect the proliferative capacity of P53-R273H (FL)-mutant CALU-1 cells or wild-type CALU-1 cells [1]. PMV6-PEG4-BI2536 (1.5 μM; 1 day) upregulates Caspase 3/7 activity and induces apoptosis in TP53Y220C-mutant 293T cells[1]. PMV6-PEG4-BI2536 (0.75-1.5 μM; 1 day) increases the proportion of early and late apoptotic cells in TP53Y220C-mutant 293T cells[1]. PMV6-PEG4-BI2536 (0.375-1.5 μM; 1 day) induces G2/M phase arrest in TP53Y220C-mutant 293T cells synchronized with Palbociclib [1]. PMV6-PEG4-BI2536 (1.5 μM; 8.5 h) inhibits PLK1 activity in TP53Y220C-mutant 293T cells synchronized via double-thymidine block[1]. PMV6-PEG4-BI2536 (4 days) significantly inhibits the proliferation of most Y220C+ cell lines (MFE319 (IC50 = 1268.3102 nM), NUGC3 (IC50 = 1713.0956 nM), MFE296 (IC50 = 4320.9284 nM), BxPC-3 (IC50 = 8251.9582 nM)) and the Y220C- cell line MCF7 (IC50 = 1268.3102 nM). PMV6-PEG4-BI2536 has no significant effect on the proliferation of the Y220C+ cell line Huh7 (IC50 = 20000 nM) or most Y220C- cell lines (LNCaP (IC50 = 14113.1353 nM), DU145 (IC50 = 20000 nM), HepG2 (IC50 = 20000 nM)).[1]. PMV6-PEG4-BI2536 (0.16-1.25 μM; 9 days) shows no significant cytotoxic effect on TP53-knockout MFE319 cells in a co-culture system with wild-type MFE319 cells[1]. PMV6-PEG4-BI2536 (62.5-250 nM; 3 weeks) reduces the proportion of TP53Y220C-mutated 293T cells[1].
References:
[1]. Sadagopan A, et al. Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs. Nat Chem Biol. 2026 May;22(5):783-792. doi: 10.1038/s41589-025-02051-7. Epub 2025 Nov 3. Erratum in: Nat Chem Biol. 2026 May;22(5):840.