| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| 50mg | |||
| 100mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
cdk2/cyclin A (IC50 = 1.5 μM); CDK2/cyclinE (IC50 = 3.6 μM); Cdk4/cyclin D1 (IC50 = 1 nM); cdk6/cyclin D3 (IC50 = 2 nM); CDK9/Cyclin T (IC50 = 28 nM); CDK5/p35 (IC50 = 0.832 μM); CDK1/cyclinB1 (IC50 = 2.4 μM); CDK7/Cyclin H/MAT1 (IC50 = 2.4 nM); Cdk5/p25 (IC50 = 1.2 nM)
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) in complex with their cyclin partners (Cyclin D1 and Cyclin D3, respectively). |
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| ln Vitro |
Lerocyclib has a biological IC50 that is almost thirty times greater than that of CDK4/cyclin D1 and CDK9/cyclin T, making it the least selective of the CDK family for CDK9/cyclin T. In CDK4/6-dependent cells, lerociclib causes a strong and long-lasting G1 arrest at an EC50 of about 20 nM. Upon treatment with G1T38 for 24 hours, WM2664 cells that were dependent on CDK4/6 showed a dose-dependent rise in G1 phase cells. A 300-fold increase over the biological IC50 was achieved by maintaining this inhibition up to 300 nM. Lerociclib at concentrations between 30 and 1000 nM completely inhibited RB phosphorylation in WM2664 cells for a full day as compared to the vehicle control. In just one hour, G1T38 therapy decreased RB phosphorylation, and in sixteen hours, it nearly entirely suppressed it. At EC50 values as low as 23 nM, G1T38 exhibits a strong suppressive effect on the growth of several tumor cell lines, such as those from breast cancer, melanoma, leukemia, and lymphoma [1].
Lerociclib dihydrochloride (G1T38) is a potent inhibitor of CDK4/CyclinD1 and CDK6/CyclinD3 with IC50 values of 1 nM and 2 nM, respectively. It demonstrates high selectivity for CDK4/6 over other CDKs and kinases. In cell-based assays, lerociclib decreases retinoblastoma protein (RB1) phosphorylation, causes G1 cell cycle arrest, and inhibits cell proliferation in a variety of CDK4/6-dependent tumorigenic cell lines. It exhibits a low EC50 (<100 nM) in Rb-competent cell lines compared to >3 µM in Rb-null cells, confirming its on-target activity. The compound shows potent antiproliferative activity against a broad panel of cancer cell lines, particularly those that are dependent on the CDK4/6-Rb pathway. |
| ln Vivo |
Lerociclib-treated mice in this HER2+ breast cancer model showed 8% tumor shrinkage after 21 days of treatment, but the tumor burden in control animals increased by 577% during the same period of time. In the MCF7 xenograft model, mice treated with 100 mg/kg Lerociclib or palbociclib daily demonstrated tumor regression within 10 days in comparison to mice given with vehicle. Tumor growth inhibition was seen after 27 days of treatment in the groups receiving 10, 50, and 100 mg/kg of lerociclib (about 12%, 74%, and 90% inhibition, respectively). Tumor growth inhibition of 18%, 66%, and 87% was observed in the 10, 50, and 100 mg/kg dosing groups, respectively, following daily oral palbociclib treatment. It's interesting to note that at the 50 mg/kg dose, lerociclib proved to be far more effective than palbociclib. In the ER+ ZR-75-1 breast cancer xenograft model, Lerocyclib and Palbociclib at the 50 mg/kg dose showed comparable outcomes. Lerociclib alone is quite successful in this NSCLC tumor model, as seen by the 77% TGI and 60% total tumor growth delay shown by Lerociclib-treated mice [1].
In vivo, lerociclib demonstrates equivalent or improved tumor efficacy compared to other CDK4/6 inhibitors in preclinical models. Daily oral treatment with lerociclib causes significant, durable growth inhibition of tumors in a HER2/neu genetically engineered mouse model (GEMM) and in MCF7 xenograft breast cancer models. The compound exhibits robust antitumor activity as a single agent and in combination with other therapies, such as endocrine therapies (e.g., fulvestrant) and targeted agents. Its favorable pharmacokinetic profile supports once- or twice-daily oral dosing regimens, leading to sustained target inhibition and tumor growth suppression. The compound is currently being evaluated in clinical trials for patients with advanced breast cancer and other solid tumors. |
| Enzyme Assay |
Biochemical profiling of G1T38 against CDK family kinases was performed using microfluidic kinase detection technology. The compounds were tested in a 12-point dose response format in singlicate at the Km concentration for ATP. The phosphoacceptor substrate peptide concentration used was 1 μM. Staurosporine was used as the reference compound for all assays.
CDK4/6 kinase activity is assessed using in vitro biochemical assays. Recombinant CDK4/CyclinD1 or CDK6/CyclinD3 enzymes are incubated with a peptide substrate and ATP in the presence of varying concentrations of lerociclib. Kinase activity is measured by quantifying the incorporation of radioactive phosphate (e.g., using 33P-ATP) into the substrate or by using luminescence-based assays (e.g., ADP-Glo). IC50 values are calculated from dose-response curves by nonlinear regression analysis. Selectivity is evaluated by profiling the compound against a broad panel of kinases. |
| Cell Assay |
To assess cell cycle effects, HS68, WM2664 (CDK4/6-dependent), and A2058 (CDK4/6-independent) cell lines were treated with G1T38. After treatment, cells were analyzed for cell cycle distribution.
To assess effects on RB phosphorylation, WM2664 cells were treated with varying doses of G1T38 for 24 hours or with 300 nM G1T38 for various time points. After treatment, cells were harvested and whole cell extracts were prepared. Total protein concentration was determined. Protein samples were heat denatured, resolved by SDS-PAGE, and transferred to a nitrocellulose membrane. Membranes were blocked and incubated overnight with primary antibodies against phospho-RB (Ser807/811), total RB, and α-tubulin (loading control). After incubation with fluorescent secondary antibodies, blots were imaged.
To assess anti-proliferative activity, various tumor cell lines were seeded in 96-well plates. After 24 hours, plates were dosed with G1T38 in a nine-point dose concentration series from 10 μM to 1 nM. Cell viability was determined after four or six days using a luminescent cell viability assay following the manufacturer's recommendations. Plates were read on a multi-mode plate reader and data analyzed.
Cellular activity is evaluated in CDK4/6-dependent cancer cell lines, such as MCF7 (breast cancer) and other Rb-proficient cell lines. Cells are treated with lerociclib at various concentrations (typically 0.001-10 µM) for 72 hours or longer. Cell proliferation is measured using MTT, MTS, or CellTiter-Glo assays. Cell cycle distribution is analyzed by flow cytometry after propidium iodide staining to assess G1 arrest. Retinoblastoma protein (Rb) phosphorylation is assessed by Western blot using phospho-specific antibodies (e.g., p-Rb Ser780/Ser807/811) to confirm target engagement and pathway modulation. Apoptosis may be measured by caspase-3/7 activation or Annexin V staining. |
| Animal Protocol |
Mice: Lerocyclib (G1T38) (100 mpk, medicated diet) is tested in female MMTV-NEU mice. Body composition is evaluated at the start of treatment, and weight measurements (in grams) are kept track of and used to calculate gross toxicity. NSCLC PDX CTG0159 tumors are implanted in female naked mice. After tumors reach a volume between 150 and 300 mm3, mice are randomly assigned to treatment groups, and dosing is started. Lerociclib (G1T38) at a dose of 100 mg/kg or the vehicle is taken orally for 28 days in a row. A lung adenocarcinoma model of H1975 NSC is implanted into female NCI Ath/nu mice. When tumors are 100–150 mm3 in size on average, mice are randomly assigned to treatment groups. For the duration of the study, mice are given oral doses of afatinib (20 mg/kg), erlotinib (70 mg/kg), or Lerociclib (50 or 100 mg/kg) either alone or in combination (Lerociclib+erlotinib or Lerociclib+afatinib). Up until the mice reach a tumor burden of 1500 mm3, all tumors are measured twice a week.
In vivo efficacy is studied in mouse xenograft models of breast cancer (e.g., MCF7, patient-derived xenografts) and other CDK4/6-dependent tumors. Lerociclib is administered orally at various doses (e.g., 50-200 mg/kg) once or twice daily. Tumor growth is measured by caliper twice weekly, and tumor volume is calculated. At study termination, tumors are excised and weighed. Pharmacodynamic markers including Rb phosphorylation and Ki-67 expression are assessed in tumor tissue by immunohistochemistry or Western blot. Pharmacokinetic parameters are measured in plasma and tumor tissue to establish PK/PD relationships. |
| ADME/Pharmacokinetics |
In tumor-bearing mice, after a single oral dose of 100 mg/kg G1T38, drug concentrations were 17-fold higher in tumors compared to plasma. Drug was detectable in tumors at 48 hours (∼65 ng/ml) while no drug was detectable in plasma at that time.
G1T38 has a relatively short plasma half-life with minimal accumulation upon repeat dosing in mice.
In mice treated daily for 7 days, plasma concentrations of G1T38 24 hours after the final dose were ∼11 ng/ml (∼22 nM). In contrast, palbociclib concentrations under the same conditions were ∼300 ng/ml (∼600 nM).
In beagle dogs dosed daily for 28 days, there was no accumulation of G1T38 as measured by pharmacokinetics.
Lerociclib dihydrochloride (G1T38) is orally bioavailable with a molecular weight of 547.52 g/mol. The compound has a molecular formula of C26H36Cl2N8O. It is soluble in DMSO and should be stored as a powder at -20°C for up to 3 years or at 4°C for 2 years. In solvent, it can be stored at -80°C for 6 months or at -20°C for 1 month. The compound has a favorable pharmacokinetic profile with a shorter half-life compared to some other CDK4/6 inhibitors, which may translate to reduced myelosuppression. Detailed pharmacokinetic parameters including half-life, Cmax, AUC, and oral bioavailability are available from preclinical and clinical studies. |
| Toxicity/Toxicokinetics |
In C57BL/6 mice treated daily for 28 days, G1T38 caused a dose-dependent decrease in neutrophils, with a maximal 48% decrease observed at 100 mg/kg after 28 days. The decrease was similar to that caused by palbociclib.
In the same mouse study, G1T38 did not cause a reduction in myeloid progenitor (Mac1+ Gr1+) proliferation (measured by EdU incorporation) 12 hours after 7 days of treatment at any dose, whereas palbociclib led to >50% reduction at 50 and 100 mg/kg.
In a 28-day repeat-dose GLP toxicology study in beagle dogs, oral administration of G1T38 led to dose-related decreases in hematopoiesis, including reduction in bone marrow cellularity and lymphocyte depletion. However, at clinically relevant doses, these effects were not sufficient to limit dosing to less than 28 days. No increases in infection or bleeding incidence were reported. Inhibition of hematopoiesis was reversible upon discontinuation of dosing.
Neutrophil counts in beagle dogs decreased rapidly in a dose-dependent manner during the first 14 days of G1T38 treatment but reached a steady state from days 14 to 25 and were readily reversible once dosing stopped.
Preclinical safety data indicate that lerociclib has a favorable safety profile with reduced myelosuppression compared to other CDK4/6 inhibitors due to its shorter half-life and optimized pharmacokinetic properties. In toxicology studies, the compound was generally well-tolerated at therapeutic doses. Common adverse events associated with CDK4/6 inhibitors include neutropenia, leukopenia, and fatigue. Specific toxicological profiles are available from preclinical and clinical study reports. The compound is for research use only and not for human therapeutic applications without appropriate regulatory approval. |
| References | |
| Additional Infomation |
Lerociclib is under investigation in clinical trial NCT02983071 (G1T38, a CDK 4/6 Inhibitor, in Combination With Fulvestrant in Hormone Receptor-positive, Her2-negative Locally Advanced or Metastatic Breast Cancer).
Lerociclib is an orally bioavailable inhibitor of cyclin-dependent kinase (CDK) types 4 (CDK4) and 6 (CDK6), with potential antineoplastic activity. Upon administration, lerociclib selectively inhibits CDK4 and CDK6, which inhibits the phosphorylation of retinoblastoma protein (Rb) early in the G1 phase, prevents CDK-mediated G1-S phase transition and leads to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play a key role in the regulation of both cell cycle progression from the G1-phase into the S-phase and tumor cell proliferation.
G1T38 is a novel, potent, selective, and orally bioavailable small molecule inhibitor of CDK4/6. It was designed to minimize undesirable on-target myelosuppression, potentially allowing for continuous daily dosing without the need for treatment holidays required by palbociclib. G1T38 showed high selectivity in a broad kinome screen and potent anti-proliferative activity in CDK4/6-dependent tumor models, including breast cancer and NSCLC. The compound has completed a Phase 1a healthy volunteer study (NCT02821624) and is being evaluated in a Phase 1b/2a trial in combination with fulvestrant in ER+/HER2- breast cancer patients (NCT02983071). Lerociclib (G1T38) is a second-generation CDK4/6 inhibitor that has been investigated in clinical trials for the treatment of advanced breast cancer and other solid tumors. It is not approved for clinical use. The compound has demonstrated a favorable safety profile with reduced myelosuppression, which may allow for continuous dosing and improved patient outcomes. Lerociclib is being developed as a potential therapeutic option for HR+/HER2- breast cancer, either as a single agent or in combination with endocrine therapies such as fulvestrant. Its unique pharmacokinetic properties differentiate it from other CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib. |
| Molecular Formula |
C26H36CL2N8O
|
|---|---|
| Molecular Weight |
547.523042678833
|
| Exact Mass |
546.238
|
| Elemental Analysis |
C, 57.04; H, 6.63; Cl, 12.95; N, 20.47; O, 2.92
|
| CAS # |
2097938-59-3
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| Related CAS # |
Lerociclib;1628256-23-4
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| PubChem CID |
129896913
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
37
|
| Complexity |
750
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
IUIVDLVJNPANBY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H34N8O.2ClH/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)2*1H
|
| Chemical Name |
2'-((5-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2'
|
| Synonyms |
G1T38 dihydrochloride G 1 T 38 dihydrochloride G-1-T-38
dihydrochloride G1T38 2HCl G 1 T 38 2HCl G-1-T-38 2HCl Lerociclib
HCl Lerociclib hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~5 mg/mL (~9.13 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8264 mL | 9.1321 mL | 18.2642 mL | |
| 5 mM | 0.3653 mL | 1.8264 mL | 3.6528 mL | |
| 10 mM | 0.1826 mL | 0.9132 mL | 1.8264 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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