[CAS NO. 1786438-30-9] (R)-CR8trihydrochloride
PRODUCTS SPECIFICATIONS [1786438-30-9]
DESCRIPTION [1786438-30-9]
Overview
| MDL | - |
|---|---|
| Molecular Weight | 540.92 |
| Molecular Formula | C24H32Cl3N7O |
| SMILES | CC[C@@H](NC1=NC(NCC2=CC=C(C3=NC=CC=C3)C=C2)=C4N=CN(C(C)C)C4=N1)CO.[H]Cl.[H]Cl.[H]Cl |
Summary
(R)-CR8 (CR8) trihydrochloride, a second-generation analog of Roscovitine, is a potent CDK1/2/5/7/9 inhibitor. (R)-CR8 trihydrochloride inhibits CDK1/cyclin B ( IC 50 =0.09 μM), CDK2/cyclin A (0.072 μM), CDK2/cyclin E (0.041 μM), CDK5/p25 (0.11 μM), CDK7/cyclin H (1.1 μM), CDK9/cyclin T (0.18 μM) and CK1δ/ε (0.4 μM). (R)-CR8 trihydrochloride induces apoptosis and has neuroprotective effect [1] [2] . (R)-CR8 trihydrochloride acts as a molecular glue degrader that depletes cyclin K [3] .
IC50 & Target
|
CDK1/cyclinB1 0.09 μM (IC 50 ) |
cdk2/cyclin A 0.072 μM (IC 50 ) |
CDK2/cyclinE 0.041 μM (IC 50 ) |
Cdk5/p25 0.11 μM (IC 50 ) |
CDK7/cyclin H 1.1 μM (IC 50 ) |
CDK9/Cyclin T 0.18 μM (IC 50 ) |
CK1δ/ε 0.4 μM (IC 50 ) |
In Vitro
(R)-CR8 (CR8) trihydrochloride (0.1-100 μM; 48 hours) is a potent inducer of apoptotic cell death with an IC
50
of 0.49 μM for SH-SY5Y cell line
[1]
.
(R)-CR8 trihydrochloride (0.25-10 μM) induces a dose-dependent induction of poly-(ADP-ribose)polymerase (PARP) cleavage
[1]
.
The CDK-bound form of (R)-CR8 trihydrochloride has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Apoptosis Analysis [1]
| Cell Line: | SH-SY5Y cell line |
| Concentration: | 0.1, 1, 10, 100 μM |
| Incubation Time: | 24 hours |
| Result: | Reduced cell survival in a dose-dependent manner. |
In Vivo
(R)-CR8 trihydrochloride (5 mg/Kg; i.p.) results in a significant reduction in lesion size at 28 days in histological assessment [2] .
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | Adult (10 to 12 weeks old) male Sprague-Dawley rats (310 to 330 g) [2] |
| Dosage: | 5 mg/Kg |
| Administration: | i.p. |
| Result: | Resulted in a significant reduction in lesion size. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT01687075 | Tel-Aviv Sourasky Medical Center |
Consecutive Subjects Who Are Suitable for a Coronary|Angioplasty of de Novo Lesion(s) in Native Coronary|Arteries Should be Screened for Eligibility.|A Total Number of 200 Patients Fulfilling the Selection|Criteria and Willing to Sign the Informed Consent Should|be Enrolled in the Trial.
|
October 2012 | Not Applicable |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
Solvent & Solubility
DMSO : 50 mg/mL ( 92.44 mM ; Need ultrasonic)
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 1.8487 mL | 9.2435 mL | 18.4870 mL |
| 5 mM | 0.3697 mL | 1.8487 mL | 3.6974 mL |
| 10 mM | 0.1849 mL | 0.9244 mL | 1.8487 mL |
References
- [1] Bettayeb K, et al. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene. 2008 Oct 2;27(44):5797-807.
- [2] Kabadi SV, et al. CR8, a novel inhibitor of CDK, limits microglial activation, astrocytosis, neuronal loss, and neurologic dysfunction after experimental traumatic brain injury. J Cereb Blood Flow Metab. 2014 Mar;34(3):502-13.
- [3] Słabicki M, et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K [published online ahead of print, 2020 Jun 3]. Nature. 2020;10.1038/s41586-020-2374-x.