1. Cell Cycle/DNA Damage
  2. CDK

G1T38 

Cat. No.: HY-112272
Handling Instructions

G1T38 is a potent and selective inhibitor of CDK4/6, with IC50s of 1 nM, 2 nM for CDK4/CyclinD1 and CDK6/CyclinD3, respectively.

For research use only. We do not sell to patients.

G1T38 Chemical Structure

G1T38 Chemical Structure

CAS No. : 1628256-23-4

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  • References

Description

G1T38 is a potent and selective inhibitor of CDK4/6, with IC50s of 1 nM, 2 nM for CDK4/CyclinD1 and CDK6/CyclinD3, respectively.

IC50 & Target

cdk2/cyclin A

1.5 μM (IC50)

CDK2/cyclinE

3.6 μM (IC50)

Cdk4/cyclin D1

1 nM (IC50)

cdk6/cyclin D3

2 nM (IC50)

CDK9/Cyclin T

28 nM (IC50)

CDK5/p35

0.832 μM (IC50)

CDK1/cyclinB1

2.4 μM (IC50)

CDK7/Cyclin H/MAT1

2.4 μM (IC50)

Cdk5/p25

1.2 μM (IC50)

In Vitro

Within the CDK family, G1T38 is least selective against CDK9/cyclin T, ~30 fold between CDK4/cyclin D1 and CDK9/ cyclin T at the biochemical IC50. G1T38 produces a robust and sustained G1 arrest in CDK4/6 dependent cells with an EC50 of ~20 nM. A dose dependent increase of cells in the G1 phase of the cell cycle is observed when CDK4/6 dependent WM2664 cells are treated with G1T38 for 24 hours. This arrest is maintained through 300 nM, more than 300x the biochemical IC50. WM2664 cells treated with 30-1000 nM of G1T38 for 24 hours exhibits a complete inhibition of RB phosphorylation compared to vehicle controls. Treatment with G1T38 reduces RB phosphorylation within 1 hour post-treatment and generates near complete inhibition of RB phosphorylation by 16 hours post-treatment. G1T38 produces a robust inhibition of proliferation in a diverse array of tumor cell lines including breast, melanoma, leukemia and lymphoma with EC50 concentrations as low as 23 nM[1].

In Vivo

In this HER2+ breast cancer model, Mice treated with G1T38 elicits 8% tumor regression after 21 days of treatment while control animals have a 577% increase in tumor burden over the same treatment period. Compared to the vehicle-treated mice, daily treatment with 100 mg/kg of G1T38 or palbociclib shows tumor regression within 10 days in the MCF7 xenograft model. After 27 days of treatment, tumor growth inhibition is observed in the 10, 50, and 100 mg/kg G1T38 cohorts (approximately 12%, 74%, and 90% inhibition, respectively). Daily oral palbociclib treatment causes an 18%, 66%, and 87% tumor growth inhibition in the 10, 50, and 100 mg/kg dosage cohorts, respectively. Interestingly, at 50 mg/kg, G1T38 is significantly more efficaciou than palbociclib. Similar results are seen in the ER+ZR-75-1 breast cancer xenograft model when comparing G1T38 and palbociclib at the 50 mg/kg dose. G1T38 treated mice exhibits 77% TGI with an overall 60% tumor growth delay demonstrating G1T38 alone is highly efficacious in this NSCLC tumor model.

Clinical Trial
Solvent & Solubility
In Vitro: 

10 mM in DMSO

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 2.1070 mL 10.5352 mL 21.0704 mL
5 mM 0.4214 mL 2.1070 mL 4.2141 mL
10 mM 0.2107 mL 1.0535 mL 2.1070 mL
*Please refer to the solubility information to select the appropriate solvent.
References
Cell Assay

SupT1, Daudi, MCF7, ZR-75-1, A2058, WM2664, and H69 cells are seeded at 1000 cells per well; MV-4-11 and BV173 cells are plated at 4000 cells per well; Tom-1 cells are plated at 8,000 cells per well; NALM-1 cells are plated at 20,000 cells per well in Costar 3903 96 well plates. After 24 hours, plates are dosed with G1T38 at a nine-point dose concentration from 10 μM to 1 nM. Cell viability is determined after four or six days. Plates are processed on BioTek Synergy2 multi-mode plate reader and data analyzed using GraphPad Prism 5 statistical software[1].

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

Animal Administration
[1]

Mice[1]
Female MMTV-NEU mice are used to test the efficacy of G1T38 (100 mpk, medicated diet). At time of treatment, body composition is assessed and weight measurements (in grams) are recorded and used as a measure of gross toxicity. Female nude mice are implanted with NSCLC PDX CTG0159 tumor. Mice are then randomized into treatment groups and dosing initiated once tumors reached a volume that fell within the range of 150-300 mm3. 100 mg/kg G1T38 or vehicle is orally administered for 28 consecutive days. Female NCI Ath/nu mice are implanted with H1975 NSC lung adenocarcinoma model. Once tumors reach an average size of 100-150 mm3, mice are randomized into treatment cohorts. Mice are orally administered daily afatinib (20 mg/kg), erlotinib (70 mg/kg), or G1T38 (50 or 100 mg/kg), as single agents or in combination (G1T38+erlotinib or G1T38+afatinib) for the duration of the study. All tumors are measured twice weekly until mice reach tumor burden of 1500 mm3.

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

References
Molecular Weight

474.60

Formula

C₂₆H₃₄N₈O

CAS No.

1628256-23-4

SMILES

O=C1NCC2(N3C1=CC4=CN=C(NC5=NC=C(N6CCN(C(C)C)CC6)C=C5)N=C43)CCCCC2

Storage

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

Shipping

Room temperature in continental US; may vary elsewhere

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G1T38
Cat. No.:
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Cat. No.: HY-112272