Cat. No.: HY-152179

PZ15227

PZ15227 is a potent and selective Bcl-XL PROTAC degrader with a DC₅₀ of 46 nM, and its K_i values for Bcl-XL, Bcl-2 and Bcl-w are 1.90 nM, 3.52 nM and >1 mM, respectively. PZ15227 recruits Bcl-XL to CRBN, induces polyubiquitination of Bcl-XL and promotes its proteasome-dependent degradation, thereby selectively killing senescent cells that rely on Bcl-XL for survival without causing severe thrombocytopenia. PZ15227 can be used for research related to age-related diseases, aging and renal cancer.
(Pink: Bcl-xL ligand (HY-44432); Blue: Cereblon ligand (HY-10984); Black: linker).

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CAS No.: 2143464-25-7
Formule: C₇₁H₈₂ClF₃N₁₂O₁₂S₃
Masse moléculaire:1484.13

Stockage:

Please store the product under the recommended conditions in the Certificate of Analysis.

PZ15227 Chemical Structure

CAS No.: 2143464-25-7

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Use of MCE Products

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Activité biologique
- Description
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Pureté et documentation
Références
Calculators
Help & FAQs
Classifications
Bioz

Activité biologique

Description

PZ15227 is a potent and selective Bcl-XL PROTAC degrader with a DC₅₀ of 46 nM, and its K_i values for Bcl-XL, Bcl-2 and Bcl-w are 1.90 nM, 3.52 nM and >1 mM, respectively. PZ15227 recruits Bcl-XL to CRBN, induces polyubiquitination of Bcl-XL and promotes its proteasome-dependent degradation, thereby selectively killing senescent cells that rely on Bcl-XL for survival without causing severe thrombocytopenia. PZ15227 can be used for research related to age-related diseases, aging and renal cancer^[1]^[2]^[3]. (Pink: Bcl-xL ligand (HY-44432); Blue: Cereblon ligand (HY-10984); Black: linker).

IC₅₀ & Target

^[1]

Bcl-xL

46 nM (DC₅₀)

Bcl-xL

1.90 nM (Ki)

Bcl-2

3.52 nM (Ki)

Bcl-W

> 1 mM (Ki)

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Cellular Effect

Cell Line	Type	Value	Description	References
WI-38	DC₅₀	46 nM	Bcl-xl degradation in WI38 human non-senescent fibroblast cells assessed via immunoblotting after 16 h incubation. Bcl-xl degradation in WI38 human non-senescent fibroblast cells assessed via immunoblotting after 16 h incubation.	32332723
WI-38	EC50	0.29 μM	Apoptosis induction (cell viability) in WI38 ionizing radiation-induced senescent fibroblast cells measured 72 h post-treatment. Apoptosis induction (cell viability) in WI38 ionizing radiation-induced senescent fibroblast cells measured 72 h post-treatment.	32332723
Platelet	EC50	>3 μM	Apoptosis induction (cell viability) in human platelets measured 72 h post-treatment. Apoptosis induction (cell viability) in human platelets measured 72 h post-treatment.	32332723
WI-38	EC₅₀	0.61 μM	Senolytic activity against human WI38 Ras oncogene-induced senescent cells assessed as reduction in cell viability by MTS cell viability assay. Senolytic activity against human WI38 Ras oncogene-induced senescent cells assessed as reduction in cell viability by MTS cell viability assay.	32332723
IMR-90	EC₅₀	0.30 μM	Senolytic activity against human IMR90 ionizing radiated senescent cells assessed as reduction in cell viability by MTS cell viability assay. Senolytic activity against human IMR90 ionizing radiated senescent cells assessed as reduction in cell viability by MTS cell viability assay.	32332723
Platelet	EC50	>10 μM	Reduction of human platelet viability measured via MTS assay after 24 h, 48 h, or 72 h incubation, with EC₅₀ > 10 μM. Reduction of human platelet viability measured via MTS assay after 24 h, 48 h, or 72 h incubation, with EC₅₀ > 10 μM.	32332723
WI-38	EC50	0.13 μM	Reduction of viability of WI38 replicative senescent cells after 72 h incubation measured by cell viability assay. Reduction of viability of WI38 replicative senescent cells after 72 h incubation measured by cell viability assay.	32332723
WI-38	EC50	0.61 μM	Reduction of viability of WI38 Ras oncogene-induced senescent cells after 72 h incubation measured by cell viability assay. Reduction of viability of WI38 Ras oncogene-induced senescent cells after 72 h incubation measured by cell viability assay.	32332723
WI-38	EC50	>10 μM	Reduction of viability of WI38 non-senescent cells after 72 h incubation measured by cell viability assay, with EC₅₀ > 10 μM. Reduction of viability of WI38 non-senescent cells after 72 h incubation measured by cell viability assay, with EC₅₀ > 10 μM.	32332723
IMR-90	EC50	>10 μM	Reduction of viability of IMR90 non-senescent cells after 72 h incubation measured by cell viability assay, with EC₅₀ > 10 μM. Reduction of viability of IMR90 non-senescent cells after 72 h incubation measured by cell viability assay, with EC₅₀ > 10 μM.	32332723

In Vitro

PZ15227 (1 μM; 4 h) selectively induces ubiquitination of Flag-Bcl-XL in 293T cells without affecting Flag-Bcl-2^[1].

PZ15227 (0.01-10 μM; 72 h) selectively kills senescent cells in WI38 (NCs, IR-SCs, RE-SCs, Ras-SCs), IMR90 (NCs, IR-SCs), REC (NCs, IR-SCs) and PAC (NCs, IR-SCs) cells, with extremely low toxicity to non-senescent cells (NCs) and platelets^[1].
PZ15227 (0.125-0.5 μM; 72 h) exerts Caspase-dependent pro-apoptotic effects on senescent cells in WI38 cells (NCs and IR-SCs)^[1].
PZ15227 efficiently and selectively degrades Bcl-XL in non-senescent WI38 human fibroblasts, while exhibiting extremely low activity against Bcl-2 and Bcl-w^[1].
PZ15227 (0.037-3 μM; 1-48 h) induces dose- and time-dependent degradation of Bcl-XL protein (DC₅₀ = 46 nM, Dmax = 96.2%) in non-senescent human WI38 fibroblasts without affecting Bcl-2 and Bcl-w, while it does not exhibit Bcl-XL-degrading activity in human platelets (PLTs)^[1].
PZ15227 (1 μM; removed by elution after 16 h of treatment; observed for 1-48 h) induces persistent and reversible degradation of Bcl-XL in WI38 cells^[1].
PZ15227 (0.04-3.0 μM) exhibits no activity in degrading other CRBN substrates (such as GS, CK1α, IKZF1, IKZF3) in 293T and WI38 cells^[1].
PZ15227 (30 nM-3.0 μM; 16 h) exerts no degradation effect on Bcl-XL, Bcl-2, Mcl-1 and CRBN proteins in mouse and human platelets^[1].
PZ15227 (12 nM-3 μM; 16 h) dose-dependently induces Bcl-XL degradation in Renca cells^[3].

PZ15227 (1 pM-0.01 μM; 72 h) exhibits no significant cytotoxicity in MC38, 4T1, Py8119 and Renca tumor cell lines^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Western Blot Analysis^[1]

Cell Line:

WI38 (NCs and IR-SCs) cells, human and mouse platelets (PLTs)
Concentration:

0.037, 0.111, 0.333, 1, 3 μM
Incubation Time:

16 h
Result:

Dose-dependently induced Bcl-XL protein degradation in WI38 cells, but did not degrade Bcl-2 and Bcl-w, nor did it cause Bcl-XL degradation in human and mouse platelets.

Apoptosis Analysis^[1]

Cell Line:

WI38 cells (NCs and IR-SCs)
Concentration:

0.125, 0.25, 0.5 μM
Incubation Time:

72 h
Result:

Dose-dependently induced apoptosis of WI38 IR-SCs, but did not induce apoptosis in NCs, and this apoptotic effect could be completely blocked by the pan-caspase inhibitor QVD.

Parmacokinetics

Species	Dose	Route	C_max	T_1/2	AUC_0-t	CL	V_ss	T_max	F
Mice^[1]	20 mg/kg	i.p.	20967 ng/mL	7.1 h	89567 ng·h/mL	/	/	0.42 h	65.1 %
Mice^[1]	2 mg/kg	i.v.	44322 ng/mL	5.8 h	13756 ng·h/mL	2.40 mL/min/kg	0.219 L/kg	/	/
Mice^[1]	20 mg/kg	p.o.	11.3 ng/mL	/	137 ng·h/mL	/	/	2.0 h	0.1 %

In Vivo

PZ15227 (30 mg/kg; i.p.; once every 4 days) exerts tumor growth inhibitory effects in immunocompetent syngeneic Renca tumor mouse models^[3].
PZ15227 (41 μmol/kg; i.p.; once every 3 days, 7 times total; 21 days of treatment) effectively clears senescent cells, restores the vitality of tissue stem cells and progenitor cells, and does not induce severe thrombocytopenia in the naturally aged mouse model^[1].
PZ15227 (41 μmol/kg; i.p.; once every 3 days, 7 times total; 3 weeks of treatment) effectively clears senescent cells in the lungs without causing significant thrombocytopenia in a total body irradiation (TBI)-induced senescent mouse model^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

C57BL/6J mice (20-month-old, male and female, naturally aged)
^[1]
Dosage:

41 μmol/kg
Administration:

i.p.; once every 3 days for 7 injections; treated and monitored for approximately 21 days
Result:

Effectively cleared senescent cells and restore the vitality of tissue stem and progenitor cells without causing severe thrombocytopenia.

Animal Model:

p16-3MR transgenic mice (2-3 months old) were exposed to a sublethal dose (6.5 Gy) of total body irradiation to induce premature senescence, and the experiment started 15 weeks after TBI^[1]
Dosage:

41 μmol/kg
Administration:

i.p.; once every 3 days for 7 injections; treated and monitored for approximately 21 days
Result:

Effectively cleared senescent cells from the lungs without causing significant thrombocytopenia.

Chemical Information

CAS No. 2143464-25-7
Masse moléculaire 1484.13
Formule C₇₁H₈₂ClF₃N₁₂O₁₂S₃
SMILES

O=S(NC(C(C=C1)=CC=C1N2CCN(CC2)CC(CC(C)(CC3)C)=C3C4=CC=C(Cl)C=C4)=O)(C5=CC(S(=O)(C(F)(F)F)=O)=C(N[C@H](CCN6CCN(C(CCCN7N=NC(COCCOCCNC8=C9C(C(N(C9=O)C%10CCC(NC%10=O)=O)=O)=CC=C8)=C7)=O)CC6)CSC%11=CC=CC=C%11)C=C5)=O
Livraison

Room temperature in continental US; may vary elsewhere.
Stockage

Please store the product under the recommended conditions in the Certificate of Analysis.

Pureté et documentation

Instruction de manipulation (2659 KB)

Références

[1]. He Y, et al. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications. 2020 Apr 24;11(1):1996.

[2]. Kolb R, et al. Proteolysis-targeting chimera against BCL-X destroys tumor-infiltrating regulatory T cells. Nature communications. 2021 Feb 24;12(1):1281.

[3]. Negi A, et al. Strategies to Reduce the On-Target Platelet Toxicity of Bcl-x Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches. Chembiochem : a European journal of chemical biology. 2022 Jun 20;23(12):e202100689. [Content Brief]

Calculators

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Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

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PZ15227

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