Synonym
G1T38; G1T-38; G1T 38; G1-T38; G1 T-38; G1 T38; Lerociclib
IUPAC/Chemical Name
2'-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
InChi Key
YPJRHEKCFKOVRT-UHFFFAOYSA-N
InChi Code
InChI=1S/C26H34N8O/c1-18(2)32-10-12-33(13-11-32)20-6-7-22(27-16-20)30-25-28-15-19-14-21-24(35)29-17-26(8-4-3-5-9-26)34(21)23(19)31-25/h6-7,14-16,18H,3-5,8-13,17H2,1-2H3,(H,29,35)(H,27,28,30,31)
SMILES Code
CC(C)N(CC1)CCN1C(C=N2)=CC=C2NC3=NC=C4C(N(C5(CCCCC5)CNC6=O)C6=C4)=N3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer.
Biological target:
Lerociclib (G1T38) is a potent and selective inhibitor of CDK4/6, with IC50s of 1 nM, 2 nM for CDK4/CyclinD1 and CDK6/CyclinD3, respectively.
In vitro activity:
To examine the therapeutic potential of G1T48, cell proliferation assays were performed using multiple ER-positive breast cancer cell lines (Fig. 3). G1T48 significantly inhibited estrogen-mediated growth of MCF7 cells demonstrating approximately threefold higher potency when compared to fulvestrant (Fig. 3a, Online Resource 5). Additionally, G1T48 and benchmark antiestrogens also inhibited the estrogen-mediated growth of ER-positive BT474 and ZR-75-1 breast cancer cells, while no growth inhibition was observed in ERnegative MDA-MB-436 breast cancer cells (Fig. 3, Online Resource 5). Furthermore, G1T48 does not impact apoptosis in MCF7 breast cancer cells. Thus, G1T48 selectively inhibits the growth of ER-positive, but not ER-negative, breast cancer cells.
Reference: Breast Cancer Res Treat. 2020; 180(3): 635–646. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103015/
In vivo activity:
The therapeutic potential of G1T48 in ER-positive primary and endocrine refractory breast cancer models was evaluated in vivo. G1T48 was first assessed, as a monotherapy or in combination with the CDK4/6 inhibitor lerociclib, for its impact on the growth of naïve MCF7 xenograft tumors (Fig. 5a). Ovariectomized estrogen-treated female nu/nu mice bearing MCF7 xenograft tumors were randomized to treatment with vehicle, lerociclib (50 mg/kg), and/or G1T48 (30 or 100 mg/kg). G1T48 treatment demonstrated dosedependent repression of tumor growth. Next, ovariectomized tamoxifen-treated mice bearing TamR xenografts were randomized to treatment with lerociclib (50 mg/kg or 100 mg/kg), G1T48 (30 mg/kg or 100 mg/kg), fulvestrant (200 mg/kg), or CDK4/6 inhibitor palbociclib (100 mg/kg) as monotherapies or a combination of lerociclib (50 mg/kg) and G1T48 (30 or 100 mg/kg). G1T48 was found to demonstrate dose-dependent inhibition of TamR tumor growth (Fig. 5c) albeit with less efficacy than fulvestrant. Interestingly, G1T48 treatment resulted in greater downregulation of intratumoral ER levels than fulvestrant despite less efficient inhibition of tumor growth.
Reference: Breast Cancer Res Treat. 2020; 180(3): 635–646. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103015
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
1.0 |
2.11 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
474.61
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Andreano KJ, Wardell SE, Baker JG, Desautels TK, Baldi R, Chao CA, Heetderks KA, Bae Y, Xiong R, Tonetti DA, Gutgesell LM, Zhao J, Sorrentino JA, Thompson DA, Bisi JE, Strum JC, Thatcher GRJ, Norris JD. G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer. Breast Cancer Res Treat. 2020 Apr;180(3):635-646. doi: 10.1007/s10549-020-05575-9. Epub 2020 Mar 4. PMID: 32130619; PMCID: PMC7103015.
In vitro protocol:
1. Andreano KJ, Wardell SE, Baker JG, Desautels TK, Baldi R, Chao CA, Heetderks KA, Bae Y, Xiong R, Tonetti DA, Gutgesell LM, Zhao J, Sorrentino JA, Thompson DA, Bisi JE, Strum JC, Thatcher GRJ, Norris JD. G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer. Breast Cancer Res Treat. 2020 Apr;180(3):635-646. doi: 10.1007/s10549-020-05575-9. Epub 2020 Mar 4. PMID: 32130619; PMCID: PMC7103015.
In vivo protocol:
1. Andreano KJ, Wardell SE, Baker JG, Desautels TK, Baldi R, Chao CA, Heetderks KA, Bae Y, Xiong R, Tonetti DA, Gutgesell LM, Zhao J, Sorrentino JA, Thompson DA, Bisi JE, Strum JC, Thatcher GRJ, Norris JD. G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer. Breast Cancer Res Treat. 2020 Apr;180(3):635-646. doi: 10.1007/s10549-020-05575-9. Epub 2020 Mar 4. PMID: 32130619; PMCID: PMC7103015.
1: Bisi JE, Sorrentino JA, Jordan JL, Darr DD, Roberts PJ, Tavares FX, Strum JC. Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget. 2017 Jun 27;8(26):42343-42358. doi: 10.18632/oncotarget.16216. PubMed PMID: 28418845; PubMed Central PMCID: PMC5522071.
2: Stice JP, Wardell SE, Norris JD, Yllanes AP, Alley HM, Haney VO, White HS, Safi R, Winter PS, Cocce KJ, Kishton RJ, Lawrence SA, Strum JC, McDonnell DP. CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC. Mol Cancer Res. 2017 Jun;15(6):660-669. doi: 10.1158/1541-7786.MCR-17-0028. Epub 2017 Feb 16. PubMed PMID: 28209757.
