CR8 hydrochloride
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MedKoo CAT#: 406333

CAS#: 1786438-30-9 (HCl)

Description: CR8 is a potent and selective inhibitor of CDK. CR8 is a more potent pyridyl analogue of roscovitine. In comparison to roscovirtine, the compound gains in potency toward CK1, which is involved in amyloid-β formation. The R-CR8 enantiomer is slightly more potent than S. CR8 is around 30 times more potent at cellular assay then roscovitine.

Chemical Structure

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CR8 hydrochloride
CAS# 1786438-30-9 (HCl)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 406333
Name: CR8 hydrochloride
CAS#: 1786438-30-9 (HCl)
Chemical Formula: C24H32Cl3N7O
Exact Mass: 431.24
Molecular Weight: 540.918
Elemental Analysis: C, 53.29; H, 5.96; Cl, 19.66; N, 18.13; O, 2.96

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1350 Ready to ship
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Related CAS #: 1786438-30-9 (HCl)   294646-77-8 (free base)  

Synonym: (R)-CR8; (R)-CR-8; (R)-CR 8; CR8; CR-8; CR 8; CR8 CDK inhibitor; CR8 CDK inhibitor HCl; CR8 CDK inhibitor hydrochloride; (R)-CR8 trihydrochloride;

IUPAC/Chemical Name: (R)-2-((9-isopropyl-6-((4-(pyridin-2-yl)benzyl)amino)-9H-purin-2-yl)amino)butan-1-ol trihydrochloride

InChi Key: ORYSYXHQFOWNDK-RGFWRHHQSA-N

InChi Code: InChI=1S/C24H29N7O.3ClH/c1-4-19(14-32)28-24-29-22(21-23(30-24)31(15-27-21)16(2)3)26-13-17-8-10-18(11-9-17)20-7-5-6-12-25-20;;;/h5-12,15-16,19,32H,4,13-14H2,1-3H3,(H2,26,28,29,30);3*1H/t19-;;;/m1.../s1

SMILES Code: 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

Appearance: Solid powder

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, not in water

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:         

Biological target: (R)-CR8 (CR8) trihydrochloride, a second-generation analog of Roscovitine, is a potent CDK1/2/5/7/9 inhibitor that inhibits CDK1/cyclin B (IC50=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).
In vitro activity: CR8 is a pleiotropic CDK inhibitor reported to bind CDK1/2/3/5/7/9/126,19, yet in cells selective cycK destabilization was observed in the presence of the drug. As cycK is reported to associate with CDK9, CDK12, and CDK1319, it was tested whether the other cycK-dependent kinases are also recruited to DDB1. The closely related CDK13 (90.8 % sequence identity), but not the more divergent CDK9 (45.5 % sequence identity) (Extended Data Fig. 7a–c), was recruited to DDB1 in the presence of CR8, albeit with a lower binding affinity (Extended Data Fig. 7d–f). Analogously, less productive in vitro cycK ubiquitination was observed for CDK13 compared to CDK12 (Extended Data Fig. 7g). The key difference between CDK9 and CDK12/13 primary sequence lies in the Cterminal extension (Extended Data Fig. 7a,b), which in this structure nestles up against DDB1 BPA and BPC propellers (Fig. 2d, Extended Data Fig. 5i). Mutations in, or truncation of, the CDK12 C-terminal extension (Extended Data Fig. 5c) abolished basal binding between CDK12 and DDB1, whereas complex formation could still be facilitated by CR8 to a varying extent (Extended Data Fig. 7h,i). Hence, the data show that the pan-selective CDK inhibitor CR8 induces specific protein-protein interactions between CDK12/13 and DDB1 and suggest that the C-terminal extension, while contributing to binding, is not essential for drug-dependent kinase recruitment. Reference: Nature. 2020 Sep; 585(7824): 293–297. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486275/
In vivo activity: To evaluate the effect of CR8 treatment on post-traumatic CCA, TBI-injured mice were administered CR8 or a vehicle by intracerebroventricular injection at 30 minutes post-TBI, and cortical tissue was collected at 6 h post-TBI for Western blot analysis. Cyclin A and cyclin B1 expression was significantly increased at 6 h after TBI (Fig. 2a, b [cyclin A]; 2a, 2c [cyclin B1]; p < 0.001 vs sham). Notably, CR8 treatment significantly attenuated the expression of both cyclins A and B1 (p < 0.01 and p < 0.05, respectively, vs vehicle). Cyclins A and B1 activate CDK1; therefore, to examine its activity, the levels of phospho-n-myc, a CDK1 substrate were measured. The data demonstrated increased levels of phospho-n-myc following TBI (Fig. 2a, d; p < 0.001 vs sham); CR8 treatment significantly attenuated these changes (p < 0.01 vs vehicle). To assess the effect of CR8 on markers of apoptosis, the presence of cleaved fragments of fodrin was assessed in these samples. TBI significantly increased fodrin cleavage (Fig. 2a, e; p < 0.001 vs sham), as demonstrated by increased levels of the 145/150 kDa cleavage product. Notably, CR8 treatment significantly decreased the level of the 145/150 kDa product when compared with vehicle-treated samples (p < 0.01 vs vehicle). Reference: Neurotherapeutics. 2012 Apr; 9(2): 405–421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324621/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 58.0 107.23

Preparing Stock Solutions

The following data is based on the product molecular weight 540.92 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.

Recalculate based on batch purity %
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. Słabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020 Sep;585(7824):293-297. doi: 10.1038/s41586-020-2374-x. Epub 2020 Jun 3. PMID: 32494016; PMCID: PMC7486275. 2. Bettayeb K, Baunbæk D, Delehouze C, Loaëc N, Hole AJ, Baumli S, Endicott JA, Douc-Rasy S, Bénard J, Oumata N, Galons H, Meijer L. CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells. Genes Cancer. 2010 Apr;1(4):369-80. doi: 10.1177/1947601910369817. PMID: 21779453; PMCID: PMC3092200. 3. Kabadi SV, Stoica BA, Hanscom M, Loane DJ, Kharebava G, Murray Ii MG, Cabatbat RM, Faden AI. CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury. Neurotherapeutics. 2012 Apr;9(2):405-21. doi: 10.1007/s13311-011-0095-4. PMID: 22167461; PMCID: PMC3324621. 4. Huang BY, Huang HB, Zhang ZJ, Liu ZG, Luo J, Liu M, Luo T. Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8. CNS Neurosci Ther. 2019 May;25(5):612-620. doi: 10.1111/cns.13090. Epub 2019 Jan 24. PMID: 30676695; PMCID: PMC6488878.
In vitro protocol: 1. Słabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020 Sep;585(7824):293-297. doi: 10.1038/s41586-020-2374-x. Epub 2020 Jun 3. PMID: 32494016; PMCID: PMC7486275. 2. Bettayeb K, Baunbæk D, Delehouze C, Loaëc N, Hole AJ, Baumli S, Endicott JA, Douc-Rasy S, Bénard J, Oumata N, Galons H, Meijer L. CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells. Genes Cancer. 2010 Apr;1(4):369-80. doi: 10.1177/1947601910369817. PMID: 21779453; PMCID: PMC3092200.
In vivo protocol: 1. Kabadi SV, Stoica BA, Hanscom M, Loane DJ, Kharebava G, Murray Ii MG, Cabatbat RM, Faden AI. CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury. Neurotherapeutics. 2012 Apr;9(2):405-21. doi: 10.1007/s13311-011-0095-4. PMID: 22167461; PMCID: PMC3324621. 2. Huang BY, Huang HB, Zhang ZJ, Liu ZG, Luo J, Liu M, Luo T. Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8. CNS Neurosci Ther. 2019 May;25(5):612-620. doi: 10.1111/cns.13090. Epub 2019 Jan 24. PMID: 30676695; PMCID: PMC6488878.

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1: Słabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020 Jun 3. doi: 10.1038/s41586-020-2374-x. Epub ahead of print. PMID: 32494016.


2: Bettayeb K, Oumata N, Echalier A, Ferandin Y, Endicott JA, Galons H, Meijer L. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin- dependent kinases. Oncogene. 2008 Oct 2;27(44):5797-807. doi: 10.1038/onc.2008.191. Epub 2008 Jun 23. PMID: 18574471.


3: Kabadi SV, Stoica BA, Hanscom M, Loane DJ, Kharebava G, Murray Ii MG, Cabatbat RM, Faden AI. CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury. Neurotherapeutics. 2012 Apr;9(2):405-21. doi: 10.1007/s13311-011-0095-4. PMID: 22167461; PMCID: PMC3324621.


4: Sallam H, El-Serafi I, Meijer L, Hassan M. Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice. BMC Pharmacol Toxicol. 2013 Sep 30;14:50. doi: 10.1186/2050-6511-14-50. PMID: 24079553; PMCID: PMC3849647.


5: Bettayeb K, Baunbæk D, Delehouze C, Loaëc N, Hole AJ, Baumli S, Endicott JA, Douc-Rasy S, Bénard J, Oumata N, Galons H, Meijer L. CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells. Genes Cancer. 2010 Apr;1(4):369-80. doi: 10.1177/1947601910369817. PMID: 21779453; PMCID: PMC3092200.


6: Goulding SP, de Guglielmo G, Carrette LLG, George O, Contet C. Systemic Administration of the Cyclin-Dependent Kinase Inhibitor (S)-CR8 Selectively Reduces Escalated Ethanol Intake in Dependent Rats. Alcohol Clin Exp Res. 2019 Oct;43(10):2079-2089. doi: 10.1111/acer.14177. Epub 2019 Aug 30. PMID: 31403700; PMCID: PMC6779498.


7: Beadling C, Cereseto A, Fan W, Naramura M, Smith KA. Cytokine response gene 8 (CR8) regulates the cell cycle G1-S phase transition and promotes cellular survival. Oncogene. 2001 Mar 29;20(14):1771-83. doi: 10.1038/sj.onc.1204212. PMID: 11313924.


8: Troadec S, Blairvacq M, Oumata N, Galons H, Meijer L, Berthou C. Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines. J Biomed Sci. 2015 Jul 17;22(1):57. doi: 10.1186/s12929-015-0163-x. PMID: 26184865; PMCID: PMC4504225.


9: Delehouzé C, Godl K, Loaëc N, Bruyère C, Desban N, Oumata N, Galons H, Roumeliotis TI, Giannopoulou EG, Grenet J, Twitchell D, Lahti J, Mouchet N, Galibert MD, Garbis SD, Meijer L. CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells. Oncogene. 2014 Dec 11;33(50):5675-87. doi: 10.1038/onc.2013.513. Epub 2013 Dec 9. PMID: 24317512; PMCID: PMC4087096.


10: Kabadi SV, Stoica BA, Loane DJ, Luo T, Faden AI. 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. doi: 10.1038/jcbfm.2013.228. Epub 2014 Jan 8. PMID: 24398934; PMCID: PMC3948132.


11: Billot K, Coquil C, Villiers B, Josselin-Foll B, Desban N, Delehouzé C, Oumata N, Le Meur Y, Boletta A, Weimbs T, Grosch M, Witzgall R, Saunier S, Fischer E, Pontoglio M, Fautrel A, Mrug M, Wallace D, Tran PV, Trudel M, Bukanov N, Ibraghimov-Beskrovnaya O, Meijer L. Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8. Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F57-F73. doi: 10.1152/ajprenal.00489.2017. Epub 2018 Mar 14. PMID: 29537311; PMCID: PMC6087785.


12: Cosimo E, McCaig AM, Carter-Brzezinski LJ, Wheadon H, Leach MT, Le Ster K, Berthou C, Durieu E, Oumata N, Galons H, Meijer L, Michie AM. Inhibition of NF- κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes prosurvival stimuli to induce apoptosis in chronic lymphocytic leukemia cells. Clin Cancer Res. 2013 May 1;19(9):2393-405. doi: 10.1158/1078-0432.CCR-12-2170. Epub 2013 Mar 26. PMID: 23532892.


13: Liu YY, Wang GP, Peng Z, Guo JY, Wu Q, Xie J, Gong SS. E2F1-CDK1 pathway activation in kanamycin-induced spiral ganglion cell apoptosis and the protective effect of CR8. Neurosci Lett. 2016 Mar 23;617:247-53. doi: 10.1016/j.neulet.2016.02.034. Epub 2016 Feb 22. PMID: 26905670.


14: Toribio AL, Pickard D, Cerdeño-Tárraga AM, Petty NK, Thomson N, Salmond G, Dougan G. Complete Genome Sequences of Two Citrobacter rodentium Bacteriophages, CR8 and CR44b. Genome Announc. 2014 May 29;2(3):e00146-14. doi: 10.1128/genomeA.00146-14. PMID: 24874665; PMCID: PMC4038870.


15: Huang BY, Huang HB, Zhang ZJ, Liu ZG, Luo J, Liu M, Luo T. Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8. CNS Neurosci Ther. 2019 May;25(5):612-620. doi: 10.1111/cns.13090. Epub 2019 Jan 24. PMID: 30676695; PMCID: PMC6488878.


16: Bukanov NO, Moreno SE, Natoli TA, Rogers KA, Smith LA, Ledbetter SR, Oumata N, Galons H, Meijer L, Ibraghimov-Beskrovnaya O. CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. Cell Cycle. 2012 Nov 1;11(21):4040-6. doi: 10.4161/cc.22375. Epub 2012 Oct 3. PMID: 23032260; PMCID: PMC3507499.


17: Kobayashi Y, Watanabe T, Inoue Y, Arakawa H, Mochizuki H, Tokuyama K, Morikawa A. CR8-194--A case of fulminated fatal disseminated Varicella Zoster virus infection with severe pulmonary damage. Paediatr Respir Rev. 2006;7 Suppl 1:S328. doi: 10.1016/j.prrv.2006.04.148. PMID: 17036409.


18: Baker ML, Lancaster T, Chiesa A, Amoretti G, Baker PJ, Barker C, Blundell SJ, Carretta S, Collison D, Güdel HU, Guidi T, McInnes EJ, Möller JS, Mutka H, Ollivier J, Pratt FL, Santini P, Tuna F, Tregenna-Piggott PL, Vitorica-Yrezabal IJ, Timco GA, Winpenny RE. Studies of a Large Odd-Numbered Odd-Electron Metal Ring: Inelastic Neutron Scattering and Muon Spin Relaxation Spectroscopy of Cr8 Mn. Chemistry. 2016 Jan 26;22(5):1779-88. doi: 10.1002/chem.201503431. Epub 2016 Jan 8. PMID: 26748964; PMCID: PMC4744977.


19: Vaknin D, Garlea VO, Demmel F, Mamontov E, Nojiri H, Martin C, Chiorescu I, Qiu Y, Kögerler P, Fielden J, Engelhardt L, Rainey C, Luban M. Level crossings and zero-field splitting in the {Cr8}-cubane spin cluster studied using inelastic neutron scattering and magnetization. J Phys Condens Matter. 2010 Nov 24;22(46):466001. doi: 10.1088/0953-8984/22/46/466001. Epub 2010 Oct 29. PMID: 21403379.


20: Waldmann O, Guidi T, Carretta S, Mondelli C, Dearden AL. Elementary excitations in the cyclic molecular nanomagnet Cr8. Phys Rev Lett. 2003 Dec 5;91(23):237202. doi: 10.1103/PhysRevLett.91.237202. Epub 2003 Dec 4. PMID: 14683210.