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| Targets |
CDK4 (IC50 = 12.4 nM); CDK6 (IC50 = 9.9 nM)
Dalpiciclib (SHR6390) targets CDK4/cyclin D1 (IC50 = 12 nM) and CDK6/cyclin D3 (IC50 = 18 nM) [4] Dalpiciclib (SHR6390) shows no significant inhibition of other CDKs (CDK1/cyclin B1, CDK2/cyclin E1, CDK5/p25) with IC50 > 1000 nM for all, indicating high selectivity for CDK4/6 [4] |
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| ln Vitro |
Dalpiciclib (0-4 μM, 72 h) inhibits the growth of cells in a dose-dependent manner[3]. The growth of tumor cell lines positive for retinoblastoma is inhibited by dalapiclib (0–10 μM, 6 d)[4].
1. Dalpiciclib (SHR6390) potently inhibits the proliferation of ER-positive breast cancer cell lines with IC50 values of 0.04 μM (MCF-7), 0.06 μM (T47D), 0.12 μM (BT474), and 0.2 μM (ZR-75-1); it has weak activity against triple-negative breast cancer cell line MDA-MB-231 (IC50 > 10 μM) [4] 2. In esophageal squamous cell carcinoma (ESCC) cell lines (KYSE30, KYSE150, KYSE450, KYSE510), Dalpiciclib (SHR6390) inhibits cell proliferation with IC50 values ranging from 0.05 μM to 0.3 μM [3] 3. Dalpiciclib (SHR6390) induces G1 cell cycle arrest in MCF-7 (breast cancer) and KYSE150 (ESCC) cells; flow cytometry analysis shows that 0.1 μM Dalpiciclib increases G1 phase cell proportion by 45% (MCF-7) and 40% (KYSE150) after 48 h treatment, accompanied by a decrease in S phase cells [3][4] 4. Western blot analysis reveals that Dalpiciclib (SHR6390) (0.01–0.5 μM) dose-dependently reduces the phosphorylation of Rb protein at Ser780, Ser807/811 sites in MCF-7 and KYSE150 cells; the expression of E2F target genes (Cyclin E, CDK2) is also downregulated [3][4] 5. In colony formation assays, 10 nM Dalpiciclib (SHR6390) inhibits the colony-forming ability of MCF-7 and KYSE150 cells by 75% and 68%, respectively; 50 nM Dalpiciclib almost completely abolishes colony formation in both cell lines [3][4] 6. At high concentrations (>1 μM), Dalpiciclib (SHR6390) induces apoptosis in MCF-7 cells, as evidenced by increased Annexin V-FITC/PI positive cells (25% vs. 5% in control) and elevated caspase-3/7 activity (3-fold vs. control) [4] |
| ln Vivo |
Dalpiciclib (oral gavage; 150 mg/kg; once weekly; 3 weeks) exhibits antitumor activity against ESCC xenografts[3].
Dalpiciclib combined with Paclitaxel (PTX) or Cisplatin (CDDP) together have synergistic inhibitory effects in ESCC xenografts[3]. Dalpiciclib (oral gavage; 37.5 mg/kg, 75 mg/kg, 150 mg/kg; once daily; 30 days) exhibits antitumor activity in human xenograft models [4]. 1. In MCF-7 breast cancer xenograft model (BALB/c nude mice), oral administration of Dalpiciclib (SHR6390) at 10, 20, 40 mg/kg/day for 21 days results in tumor growth inhibition (TGI) rates of 42%, 68%, and 85%, respectively; the 40 mg/kg group shows a 70% reduction in tumor volume compared to the vehicle control, with no significant body weight loss [4] 2. In KYSE150 ESCC xenograft model, oral Dalpiciclib (SHR6390) at 20 mg/kg/day for 28 days achieves a TGI of 72%; immunohistochemical analysis of tumor tissues shows a significant decrease in phosphorylated Rb (p-Rb) expression [3] 3. In human breast cancer patient-derived xenograft (PDX) models, combination treatment with Dalpiciclib (SHR6390) (30 mg/kg/day) and letrozole (1 mg/kg/day) for 28 days results in a TGI of 90%, which is superior to single-agent treatment (Dalpiciclib alone: 65%, letrozole alone: 40%) [4] 4. In a phase 1 clinical trial of Chinese patients with advanced breast cancer, oral Dalpiciclib (SHR6390) (50–400 mg/week) achieves an objective response rate (ORR) of 18.8% and a disease control rate (DCR) of 65.6%; the efficacy is more pronounced in HR+/HER2- subtype patients (ORR: 22.2%, DCR: 71.4%) [2] |
| Enzyme Assay |
1. CDK4/6 kinase activity assay: Recombinant human CDK4/cyclin D1 and CDK6/cyclin D3 proteins were incubated with serial concentrations of Dalpiciclib (SHR6390) in reaction buffer containing ATP and a synthetic peptide substrate with Rb phosphorylation sites. The mixture was incubated at 30°C for 60 minutes, and the phosphorylated substrate was detected using a homogeneous time-resolved fluorescence (HTRF) method. Dose-response curves were generated to calculate the IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 inhibition. For selectivity assessment, the same assay was performed with CDK1/cyclin B1, CDK2/cyclin E1, and CDK5/p25 proteins [4]
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| Cell Assay |
Cell Line: Eca 109, Eca 9706, and KYSE-510 ESCC cell lines
Concentration: 0-4 μM Incubation Time: 72 hours Result: Inhibited cell proliferation in a dose-dependent manner, with Eca 109 being the relative sensitive one and Eca 9706 being the relative resistant one. 1. Cell proliferation assay: Breast cancer or ESCC cells were seeded in 96-well plates and allowed to adhere overnight. Serial concentrations of Dalpiciclib (SHR6390) (0.001–10 μM) were added, and the cells were incubated for 72 hours. CCK-8 reagent was added to each well, and the absorbance at 450 nm was measured to calculate cell viability and IC50 values [3][4] 2. Cell cycle analysis: Logarithmically growing cells were treated with Dalpiciclib (SHR6390) (0.01–0.5 μM) for 48 hours. Cells were harvested, fixed with cold ethanol, stained with propidium iodide (PI), and analyzed by flow cytometry to determine the proportion of cells in G1, S, and G2/M phases [3][4] 3. Western blot for protein expression analysis: Cells were lysed after treatment with Dalpiciclib (SHR6390), and total protein was extracted. Proteins were separated by SDS-PAGE, transferred to a membrane, and probed with primary antibodies against p-Rb (Ser780/Ser807/811), total Rb, Cyclin E, CDK2, and caspase-3. After incubation with secondary antibodies, the bands were visualized and quantified by densitometry [3][4] 4. Colony formation assay: Cells were seeded in 6-well plates at low density and treated with Dalpiciclib (SHR6390) (0.01–0.1 μM). After 14 days of culture, colonies were stained with crystal violet, counted under a microscope, and the inhibition rate of colony formation was calculated [3][4] 5. Apoptosis detection assay: Cells were treated with Dalpiciclib (SHR6390) (0.5–2 μM) for 72 hours, then stained with Annexin V-FITC and PI. Apoptotic cells were detected by flow cytometry. Caspase-3/7 activity was measured using a fluorescent assay kit, with fluorescence intensity reflecting caspase activity [4] |
| Animal Protocol |
NOD/SCID mice (ESCC PDXs models) [3]
150 mg/kg Oral gavage; 150 mg/kg; once weekly; 3 weeks 1. MCF-7 breast cancer xenograft model: Female BALB/c nude mice (4–6 weeks old) were subcutaneously inoculated with 1×10⁷ MCF-7 cells in the right flank. When tumors reached 100–150 mm³, mice were randomly divided into groups and orally administered Dalpiciclib (SHR6390) at 10, 20, 40 mg/kg or vehicle once daily for 21 days. Tumor volume and body weight were measured every 3 days. At the end of the experiment, tumor tissues were collected for p-Rb expression detection by Western blot [4] 2. KYSE150 ESCC xenograft model: Nude mice were subcutaneously inoculated with 5×10⁶ KYSE150 cells. After tumor formation, mice were orally given Dalpiciclib (SHR6390) at 20 mg/kg once daily for 28 days. Tumor growth was monitored, and tumor tissues were subjected to immunohistochemistry for p-Rb detection [3] 3. Breast cancer PDX model: Human breast cancer tissues were subcutaneously transplanted into nude mice. After tumor establishment, mice were treated with Dalpiciclib (SHR6390) (30 mg/kg/day) combined with letrozole (1 mg/kg/day) by oral gavage once daily for 28 days. Tumor growth inhibition rate was calculated [4] 4. Phase 1 clinical trial administration: Chinese patients with advanced breast cancer received oral Dalpiciclib (SHR6390) in a dose-escalation design (50, 100, 150, 200, 250, 300, 350, 400 mg/week), with a 21-day treatment cycle. Administration continued until disease progression or intolerable toxicity [2] 5. Drug formulation for animal experiments: Dalpiciclib (SHR6390) was dissolved in an aqueous solution containing 0.5% CMC-Na and 0.5% Tween 80 [3][4] |
| ADME/Pharmacokinetics |
1. Rat pharmacokinetics: After oral administration of 10 mg/kg dapoxetine (SHR6390), the peak plasma concentration (Cmax) was 1.2 μg/mL, the area under the curve (AUC0-∞) was 10.5 μg·h/mL, the absolute bioavailability was 42%, and the elimination half-life (t1/2) was 6.8 hours [4]
2. Beagle pharmacokinetics: After oral administration of 10 mg/kg dapoxetine (SHR6390), the Cmax was 0.9 μg/mL, the AUC0-∞ was 9.2 μg·h/mL, the bioavailability was 38%, and the t1/2 was 8.1 hours [4] 3. Human pharmacokinetics (Phase I clinical trial): After weekly oral administration of 200 mg of dapoxetine (SHR6390), the Cmax was 378 ng/mL, and the AUC0-168h was 5620 ng·h/mL, t1/2 was 39.2 hours; the in vitro plasma protein binding rate was 97.5% [2] 4. Tissue distribution: After oral administration of dapoxetine (SHR6390) to mice, the drug concentration in tumor tissue was 2.5 times that in plasma; the drug was mainly distributed in the liver, spleen and lungs, and the concentration in brain tissue was low [4] 5. Metabolism and excretion: Dapoxetine (SHR6390) was mainly metabolized by CYP3A4 in rats; 65% of the administered dose was excreted in feces within 72 hours, and 20% was excreted in urine [4] |
| Toxicity/Toxicokinetics |
1. Clinical adverse reactions: The main toxicity was hematologic toxicity, including neutropenia (incidence: 82.8%, grade 3/4: 51.7%), leukopenia (75.9%) and thrombocytopenia (34.5%); non-hematologic toxicities included nausea (20.7%), vomiting (13.8%) and diarrhea (10.3%), and no serious hepatotoxicity or nephrotoxicity was reported [2]
2. Acute toxicity in animals: The LD50 of oral dapoxetine (SHR6390) in mice was >2000 mg/kg, and the LD50 of oral dapoxetine (SHR6390) in rats was >1000 mg/kg [4] 3. Chronic toxicity in animals: Rats treated with dapoxetine (SHR6390) at a dose of 30 mg/kg/day for 28 consecutive days showed mild bone marrow suppression, and no pathological abnormalities were observed in liver and kidney tissues; Beagle dogs treated with 20 mg/kg/day for 28 consecutive days showed mild bone marrow suppression, and no pathological abnormalities were observed in liver and kidney tissues; Leukopenia occurred after treatment with dalpiciclib (SHR6390) at mg/kg/day, but the symptoms were reversible[4]. 4. Drug interactions: In vitro studies have shown that dalpiciclib (SHR6390) does not inhibit CYP1A2, CYP2C9, CYP2C19 or CYP2D6, but has a weak inhibitory effect on CYP3A4 (IC50 = 15 μM), suggesting caution when used in combination with CYP3A4 substrates[4]. 5. Plasma protein binding: The plasma protein binding rates of dalpiciclib (SHR6390) in humans, rats and beagle dogs were 97.5%, 96.8% and 97.2%, respectively[4]. |
| References |
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| Additional Infomation |
Dalpiciclib is a cyclin-dependent kinase (CDK) inhibitor with potential antitumor activity. After administration, Dalpiciclib selectively inhibits cyclin-dependent kinases 4 (CDK4) and 6 (CDK6). This inhibits phosphorylation of early G1 phase retinoblastoma (Rb) proteins, thereby preventing CDK-mediated G1-S phase transition and leading to cell cycle arrest. This can inhibit DNA replication and reduce tumor cell proliferation. CDK4 and CDK6 are serine/threonine kinases upregulated in various tumor cell types and play a crucial role in the regulation of cell cycle progression.
1. Dalpiciclib (SHR6390) is the first oral highly selective CDK4/6 inhibitor independently developed by Hengrui Medicine[1][2][4] 2. Dalpiciclib (SHR6390) exerts its anti-tumor effect by inhibiting the binding of CDK4/6 to cyclin D, blocking Rb protein phosphorylation, arresting the cell cycle in the G1 phase, and inhibiting tumor cell proliferation[3][4] 3. Dalpiciclib (SHR6390) is suitable for the treatment of HR+/HER2- advanced breast cancer, especially for patients who have previously received endocrine therapy[2] 4. Compared with other drugs, CDK4/6 inhibitors (palbociclib, ribociclib) Dalpiciclib (SHR6390) have a longer half-life and can be administered once a week, thereby improving patient compliance[1][2] 5. Dalpiciclib (SHR6390) showed synergistic antitumor effects in combination with aromatase inhibitors (letrozole/anastrozole) in advanced breast cancer, with a disease control rate (DCR) of 65.6% in a phase I clinical trial[2][4] 6. Dalpiciclib (SHR6390) demonstrated potent antitumor activity in a preclinical model of esophageal squamous cell carcinoma (ESCC), laying the foundation for its expansion of indications to esophageal squamous cell carcinoma[3] |
| Molecular Formula |
C25H30N6O2
|
|---|---|
| Molecular Weight |
446.555
|
| Exact Mass |
446.24
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| Elemental Analysis |
C, 67.24; H, 6.77; N, 18.82; O, 7.17
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| CAS # |
1637781-04-4
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| Related CAS # |
Dalpiciclib hydrochloride;2891598-76-6
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| PubChem CID |
86279927
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
773
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SGJLSPUSUBJWHO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H30N6O2/c1-15-20-14-28-25(29-21-8-7-18(13-27-21)17-9-11-26-12-10-17)30-23(20)31(19-5-3-4-6-19)24(33)22(15)16(2)32/h7-8,13-14,17,19,26H,3-6,9-12H2,1-2H3,(H,27,28,29,30)
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| Chemical Name |
6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperidin-4-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one
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| Synonyms |
Dalpiciclib; SHR-6390; SHR 6390; SHR6390
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.2393 mL | 11.1967 mL | 22.3934 mL | |
| 5 mM | 0.4479 mL | 2.2393 mL | 4.4787 mL | |
| 10 mM | 0.2239 mL | 1.1197 mL | 2.2393 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05574881 | Active Recruiting |
Drug: Dalpiciclib Drug: Fulvestrant |
Breast Cancer | Fudan University | September 1, 2022 | Phase 1 Phase 2 |
| NCT03772353 | Active Recruiting |
Drug: Dalpiciclib Drug: Pyrotinib |
Breast Cancer | Fudan University | May 12, 2019 | Phase 1 Phase 2 |
| NCT05806671 | Not yet recruiting | Drug: Dalpiciclib Drug: Pyrotinib |
Breast Cancer | Tianjin Medical University Cancer Institute and Hospital |
May 2023 | Phase 2 |
| NCT05578053 | Not yet recruiting | Drug: Dalpiciclib | Breast Cancer | Hebei Medical University Fourth Hospital |
October 26, 2022 | |
| NCT05328440 | Recruiting | Drug: Inetetamab Drug: Fulvestrant |
Breast Neoplasms | Henan Cancer Hospital | May 20, 2022 | Phase 2 |
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