Art. -Nr.: HY-189225

PP-048

PP-048 is a selective dual inhibitor of Polθ/PARP1, with IC₅₀ values of 4.9 nM and 6.8 nM for the Polθ helicase/ATPase domain and PARP1, respectively. PP-048 impairs the compensatory DNA repair capacity of homologous recombination-deficient cells by simultaneously inhibiting the DNA repair functions associated with Polθ and PARP1, thereby exacerbating DNA double-strand damage and inducing apoptosis. PP-048 exhibits more potent selective antiproliferative activity against HR-deficient cancer cells. PP-048 can be used in studies related to Polθ/PARP1 dual-target inhibition, synthetic lethality, DNA damage repair, and HR-deficient triple-negative breast cancer.

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Formel: C₃₇H₃₃ClN₁₀O₃S
Molecular Weight:733.24

Speicherung:

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

PP-048 Chemical Structure

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Use of MCE Products

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

Biologische Aktivität
- Beschreibung
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Reinheit & Dokumentation
Verweise
Calculators
Help & FAQs
Classifications
Bioz

Biologische Aktivität

Beschreibung

IC₅₀ & Target

^[1]

PARP1

6.8 nM (IC₅₀)

Polθ

4.9 nM (IC₅₀)

PARP2

1542 nM (IC₅₀)

PARP3

3340 nM (IC₅₀)

PARP5A

8266 nM (IC₅₀)

PARP5B

7986 nM (IC₅₀)

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Cellular Effect

Cell Line	Type	Value	Description	References
MDA-MB-436	IC50	0.07 μM	Antiproliferative activity against BRCA1-deficient MDA-MB-436 cells assessed by CCK-8 assay after 7 days of incubation. Antiproliferative activity against BRCA1-deficient MDA-MB-436 cells assessed by CCK-8 assay after 7 days of incubation.	acs.jmedchem.6c01400
HCT-116	IC50	5.0 μM	Antiproliferative activity against BRCA2-knockout HCT116 cells assessed by CCK-8 assay after 7 days of incubation. Antiproliferative activity against BRCA2-knockout HCT116 cells assessed by CCK-8 assay after 7 days of incubation.	acs.jmedchem.6c01400
MDA-MB-231	IC50	68.4 μM	Antiproliferative activity against BRCA-proficient MDA-MB-231 cells assessed by CCK-8 assay after 7 days of incubation. Antiproliferative activity against BRCA-proficient MDA-MB-231 cells assessed by CCK-8 assay after 7 days of incubation.	acs.jmedchem.6c01400

In Vitro

OthersAnti-cancerApoptosis

Others

PP-048 inhibits the ATPase activity of the recombinant human Polθ helicase domain, with an IC₅₀ of 4.9 nM^[1].
PP-048 (10 nM-100 nM; 60 min) inhibits the enzymatic activity of full-length recombinant human PARP1, with an IC₅₀ of 6.8 nM^[1].
PP-048 (10 nM-100 μM; 1 h) exhibits a selectivity for PARP1 that is more than 226-fold higher than that for PARP2, PARP3, PARP5a, PARP5b, and PARP7, with IC₅₀ values against these corresponding off-target isoforms of 1542 nM, 3340 nM, 8266 nM, 7986 nM, and >100000 nM, respectively^[1].
PP-048 (5 μM; 2 h) simultaneously binds to PARP1 and Polθ in MDA-MB-436 cells and enhances their thermal stability, confirming its dual-target binding property in living HR-deficient cancer cells^[1].
PP-048 (1.0 μM; 0-45 min) exhibits excellent metabolic stability in human liver microsomes, with a half-life of 254.47 min and an intrinsic clearance of 6.30 mL/min/kg^[1].
PP-048 (1.0 μM; 0-60 min) exhibits excellent metabolic stability in rat liver microsomes, with a half-life of 347.22 min and an intrinsic clearance of 4.62 mL/min/kg^[1].
PP-048 (10 μM; 120 min) exhibits low passive permeability across Caco-2 cell monolayers, with an efflux ratio as high as 75.83, indicating that PP-048 is a potential P-gp substrate^[1].
PP-048 (0.5 μM; 72 h) significantly increases the number of γH2AX foci and fluorescence intensity in MDA-MB-436 cells^[1].
PP-048 (0.1 and 0.5 μM; 72 h) increases γH2AX protein levels in a dose-dependent manner^[1].

Anti-cancer

PP-048 (up to 80 μM; 7 days) exhibits potent antiproliferative activity against HR-deficient MDA-MB-436 cells, with an IC₅₀ of 0.07 μM; it shows moderate activity against BRCA2-knockout HCT116 cells, significantly reduced potency against HR-proficient MDA-MB-231 cells, and no obvious activity against non-malignant MCF-10A cells^[1].
PP-048 (0.5 μM; 9 days) almost completely inhibits the clonogenic survival of MDA-MB-436 BRCA1-deficient cells after 9 days of incubation^[1].

Apoptosis

PP-048 (0.5 μM; 72 h) induces significant apoptosis in MDA-MB-436 BRCA1-deficient cells after 3 days of incubation, and its effect is superior to that of two single-target reference inhibitors at their respective tested concentrations^[1].

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

Cell Proliferation Assay^[1]

Cell Line:

MDA-MB-436
Concentration:

0.5 μM
Incubation Time:

9 days
Result:

Almost completely suppressed colony formation.

Apoptosis Analysis^[1]

Cell Line:

MDA-MB-436
Concentration:

0.5 μM
Incubation Time:

72 h
Result:

Induced a higher level of apoptosis in MDA-MB-436 cells than treatment with reference compounds.
Increased the total apoptotic population to 22% following exposure.

Western Blot Analysis^[1]

Cell Line:

MDA-MB-436
Concentration:

0.1, 0.5 μM
Incubation Time:

72 h
Result:

Dose-dependently increased γH2AX protein levels.

Parmacokinetics

Species	Dose	Route	T_1/2	T_max	MRT_0-∞	C_max	AUC_0-t	AUC_0-∞	V_ss	V_z	CL	F
Rat^[1]	1 mg/kg	i.v.	1.9 h	0.08 h	0.3 h	13492.2 ng/mL	5545.6 ng·h/mL	5612.2 ng·h/mL	131.1 mL/kg	480.5 mL/kg	181.0 mL/h/kg	/
Rat^[1]	10 mg/kg	p.o.	0.8 h	1.0 h	2.2 h	3180.8 ng/mL	7015.9 ng·h/mL	7032.3 ng·h/mL	/	/	/	12.7 %

In Vivo

Anti-cancerOthers

Anti-cancer

PP-048 (10 mg/kg; intravenous injection; once daily; 21 days) significantly inhibits tumor growth in a BRCA1-deficient MDA-MB-436 triple-negative breast cancer xenograft model in female BALB/c nude mice, with a TGI of 91.3%. This value is higher than the 11% TGI of AB25583 (HY-162859) monotherapy, the 75.2% TGI of AZD5305 (HY-132167) monotherapy, and the 81.2% TGI of the combination therapy of the two agents. PP-048 increases γH2AX expression in MDA-MB-436 xenograft tumor tissues, and its DNA damage-associated γH2AX signal is higher than that in the AB25583, AZD5305, and combination treatment groups. PP-048 increases γH2AX expression in MDA-MB-436 xenograft tumor tissues, and its DNA damage-associated γH2AX signal is higher than that in the AB25583, AZD5305, and combination treatment groups^[1].

Others

PP-048 (1-10 mg/kg; intravenous injection; oral administration; single dose) exhibits significantly improved in vivo pharmacokinetic properties in healthy Sprague-Dawley rats, with an oral bioavailability of up to 12.7%^[1].

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

Animal Model:

BALB/c nude mice (Five-week-old female, 18-20 g)^[1]
Dosage:

10 mg/kg
Administration:

i.v.; once daily; 21 consecutive days
Result:

Achieved 91.3% TGI.
Produced greater tumor growth inhibition than AB25583 alone (TGI 11%).
Produced greater tumor growth inhibition than AZD5305 alone (TGI 75.2%).
Produced greater tumor growth inhibition than the AB25583 + AZD5305 group (TGI 81.2%).
Maintained stable body-weight changes during administration.
Showed no discernible histopathological toxicity in the heart, liver, spleen, lungs, or kidneys.
Markedly increased γH2AX expression in harvested tumor tissues.
Produced stronger tumor γH2AX staining than AB25583, AZD5305, or their combined administration.
Did not produce obvious reductions in terminal platelet counts.
Did not produce obvious reductions in terminal red blood cell counts.

Related Protocols :

Chemical Information

Molecular Weight 733.24
Formel C₃₇H₃₃ClN₁₀O₃S
SMILES

CCC1=CC2=C(NC1=O)C=C(C=N2)CN3CCN(CC3)C4=CN=C(C=C4)C#CC5=NN=C(S5)NC(C6=C(C=C(N=C6)C)C7=CC(Cl)=NC=C7OC)=O
Versand

Room temperature in continental US; may vary elsewhere.
Speicherung

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

Reinheit & Dokumentation

Handling Instructions (2659 KB)

Verweise

[1]. Ma L, et al. Optimization of a Second-Generation, Highly Selective Polθ/PARP1 Dual Inhibitor with Improved Pharmacokinetics and Potent Activity against HR-Deficient Tumors. J Med Chem. 2026. Published online August 10, 2026.

Calculators

Molaritätsrechner

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

Konzentration Konzentration

Volumen Volumen

Molecular Weight Molecular Weight

Verdünnungsrechner

Konzentration _{(Stammlösung)} × Volumen _{(Stammlösung)} = Konzentration _{(Ziellösung)} × Volumen _{(Ziellösung)}

Konzentration _{(Stammlösung)} Konzentration _{(Stammlösung)}

Volumen _{(Stammlösung)} Volumen _{(Stammlösung)}

Konzentration _{(Ziellösung)} Konzentration _{(Ziellösung)}

Volumen _{(Ziellösung)} Volumen _{(Ziellösung)}

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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PP-048

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