2. PROTAC PI3K/Akt/mTOR Apoptosis
  3. PROTACs mTOR PI3K Apoptosis
  4. GP262

GP262 is a PI3K/mTOR PROTAC degrader targeting PI3Kγ, PI3Kα and mTOR with DC50 values of 42.23 nM, 227.4 nM and 45.4 nM, respectively in MDA-MB-231 cells. GP262 induces degradation of p110α and p110γ with a DC50 of 227.4 and 42.23 nM. GP262 efficient modulates the PI3K/AKT/mTOR pathway, achieving degradation through the ubiquitin-proteasome system (UPS). GP262 also exhibits robust antiproliferative activity and induces apoptosis in vitro. GP262 exhibits tumor growth suppression capability and biosafety profile. GP262 can be used for leukemia and triple-negative breast cancer (TNBC) .

(Pink: mTOR and PI3K ligand (HY-203618); Blue: VHL ligand (HY-125845); Black: linker).

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GP262

GP262 Chemical Structure

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Description

GP262 is a PI3K/mTOR PROTAC degrader targeting PI3Kγ, PI3Kα and mTOR with DC50 values of 42.23 nM, 227.4 nM and 45.4 nM, respectively in MDA-MB-231 cells. GP262 induces degradation of p110α and p110γ with a DC50 of 227.4 and 42.23 nM. GP262 efficient modulates the PI3K/AKT/mTOR pathway, achieving degradation through the ubiquitin-proteasome system (UPS). GP262 also exhibits robust antiproliferative activity and induces apoptosis in vitro. GP262 exhibits tumor growth suppression capability and biosafety profile. GP262 can be used for leukemia and triple-negative breast cancer (TNBC) [1].
(Pink: mTOR and PI3K ligand (HY-203618); Blue: VHL ligand (HY-125845); Black: linker).

IC50 & Target[1]

p110α

227.4 nM (DC50)

p110γ

42.23 nM (ED50)

mTOR

45.4 nM (Kd)

In Vitro

GP262 (0-5 μM, 0-24 h) efficiently reduces PI3K and mTOR Levels and this degradation is attenuated upon 26S proteasome inhibition, can be blocked under high concentration competition (MG132 (HY-13259) and VH032 (HY-120217)) and depends on VHL recruitment in MDA-MB-231 cells[1].
GP262 (8-1000 nM) significantly inhibits proliferation and induces programmed cell death (apoptosis), reveals dose-dependent growth inhibition with IC50 values of 68.0 nM (in MDA-MB-231), 161.6 nM (in MCF-7), and 124.2 nM (in MDA-MB-361), achieving maximum inhibition (Imax) of 65.4, 83.4, and 97.7% respectively, impairs colony formation in MDA-MB-231 cells at 200 nM, and has a degradation efficacy against mTOR and PI3Kα with IC50 values of 167.6 and 40 nM in MCF-7 cells[1].
GP262 (8-5000 nM, 24 h) demonstrates concentration-dependent reduction of PI3Kγ protein levels in THP-1 cells and antiproliferative effects in OCI-AML3 (IC50 = 44.3 nM) and THP-1 cells (IC50 = 48.3 nM)[1].
GP262 (1000 nM, 12 h) increases apoptosis to 32.1% in MDA-MB-231 cells[1].
GP262 (0.03125-2 μM) reveals dissociation constants with Kd of 0.867 μM for PI3Kα and 0.479 μM for mTOR[1].
GP262 induces polyubiquitination-dependent proteasomal degradation[1].
GP262 exhibits excellent kinase selectivity for the PI3K family and mTOR, thereby inducing widespread transcriptomic alterations including multiple differentially expressed genes (DEGs) associated with cell cycle regulation, cancer-related processes, and apoptosis, which collectively demonstrate significant enrichment and profound impact on cell cycle-related pathways in MDA-MB-231 cells[1].

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

GP262 Related Antibodies

Western Blot Analysis[1]

Cell Line: MDA-MB-231 cells
Concentration: 8, 40, 200, 1000 and 5000 nM
Incubation Time: 0, 3, 6, 9, 12 and 24 h
Result: Induced degradation of p110α with a DC50 of 227.4 nM and a Dmax of 71.3%.
Induced degradation of p110γ with a DC50 of 42.23 nM and a Dmax of 88.6%.
Induced degradation of mTOR with a DC50 of 45.4 nM and a Dmax of 74.9%.
Significantly inhibited AKT activation (p-AKT) without affecting the total AKT protein levels.
Reduced p85, p-GSK and p-4EBP1 protein level.
Induced time-dependent proteolysis of mTOR and p110α at 1 μM, exhibiting significant degradation within 12 h and maximal efficiency by 24 h, and this effect was markedly attenuated upon 26S proteasome inhibition and was also inhibited by siRNA-mediated VHL knockdown (500 nM, 24 h).

Western Blot Analysis[1]

Cell Line: THP-1 cells
Concentration: 8, 40, 200, 1000 and 5000 nM
Incubation Time: 24 h
Result: Demonstrated concentration-dependent reduction of PI3Kγ protein levels (DC50 = 88.4 nM) with >70% maximal degradation efficiency achieved after 24-h treatment.
Parmacokinetics
Species Dose Route T1/2 Tmax Cmax AUClast AUCinf MRTINF_obs F ClF_obs C0 AUC0-inf Vd
Rat[1] 15 mg/mL i.p. 8.25 h 7.00 h 816 ng/mL 11068 ng·h/mL 12469 ng·h/mL 11.1 h 51.5 % / / / /
Rat[1] 5 mg/mL i.v. 7.6 h / / 7848 ng·h/mL / 2.68 h / 10.5 mL/min/kg 50993 ng/mL 8073 ng·h/mL 6.96 L/kg
In Vivo

GP262 (15 or 25 mg/kg, i.p., daily for 20 consecutive days) effective reduces target protein levels (PI3K and mTOR) in tumor tissues and significant tumor growth inhibition and exhibits excellent safety and tolerability without causing significant systemic toxicity or organ damage in MDA MB-231 triple-negative breast cancer xenograft NOD-SCID mice model[1].

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

Animal Model: MDA MB-231 cells induced-female NOD-SCID mice (60-70 days old, 22-24 g)[1]
Dosage: 15 or 25 mg/kg
Administration: i.p., daily for 20 consecutive days
Result: Showed 57.8% tumor growth inhibition at 15 mg/kg and 79.2% tumor growth inhibition at 25 mg/kg.
Maintained body weight fluctuations within 10%.
Reduced PI3K and mTOR protein expression.
Decreased expression of the proliferation marker KI67.
Showed no significantly inflammatory infiltration, necrosis, or structural abnormalities in major organs (heart, liver, and kidney).
Molecular Weight

1073.31

Formula

C56H72N12O8S
Appearance

Solid

SMILES

O=C(NC1=CC=C(C=C1)C(NCCCCCCCCC(N[C@H](C(N2C[C@@H](C[C@H]2C(NCC3=CC=C(C=C3)C4=C(N=CS4)C)=O)O)=O)C(C)(C)C)=O)=O)NC5=CC=C(C=C5)C6=NC(N7CCOCC7)=NC(N8CCOCC8)=N6
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (93.17 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 0.9317 mL 4.6585 mL 9.3170 mL
5 mM 0.1863 mL 0.9317 mL 1.8634 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

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Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 0.9317 mL 4.6585 mL 9.3170 mL 23.2924 mL
5 mM 0.1863 mL 0.9317 mL 1.8634 mL 4.6585 mL
10 mM 0.0932 mL 0.4658 mL 0.9317 mL 2.3292 mL
15 mM 0.0621 mL 0.3106 mL 0.6211 mL 1.5528 mL
20 mM 0.0466 mL 0.2329 mL 0.4658 mL 1.1646 mL
25 mM 0.0373 mL 0.1863 mL 0.3727 mL 0.9317 mL
30 mM 0.0311 mL 0.1553 mL 0.3106 mL 0.7764 mL
40 mM 0.0233 mL 0.1165 mL 0.2329 mL 0.5823 mL
50 mM 0.0186 mL 0.0932 mL 0.1863 mL 0.4658 mL
60 mM 0.0155 mL 0.0776 mL 0.1553 mL 0.3882 mL
80 mM 0.0116 mL 0.0582 mL 0.1165 mL 0.2912 mL
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GP262 Related Classifications

Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

GP262GP 262GP-262PROTACsmTORPI3KApoptosisMammalian target of RapamycinPhosphoinositide 3-kinasePROTACapoptosisLeukemiatriple-negative breast cancerInhibitorinhibitorinhibit

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