Synonym
CC-671; CC 671; CC671;
IUPAC/Chemical Name
4-((4-(Cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo-[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide
InChi Key
CWJLAVRXVFHDSJ-UHFFFAOYSA-N
InChi Code
InChI=1S/C28H28N6O4/c1-15-31-21-10-8-16(12-23(21)37-15)19-14-30-25-24(19)27(38-18-6-4-5-7-18)34-28(33-25)32-20-11-9-17(26(35)29-2)13-22(20)36-3/h8-14,18H,4-7H2,1-3H3,(H,29,35)(H2,30,32,33,34)
SMILES Code
O=C(NC)C1=CC=C(NC2=NC(OC3CCCC3)=C4C(NC=C4C5=CC=C6N=C(C)OC6=C5)=N2)C(OC)=C1
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
Biological target:
CC-671 is a dual TTK protein kinase/CDC2-like kinase (CLK2) inhibitor with IC50s of 0.005 and 0.006 μM for TTK and CLK2, respectively.
In vitro activity:
HCT-116 cell lysates were treated with CC-671 (compound 23) at 3 μM for 1 h and tested in the ActivX KiNative profiling assay. Only four kinases showed cellular binding of 75% or more including CLK2, CAMKK2, PIP4K22, and JNK (TTK not offered, full data in Supporting Information, Table 2). The IC50 values for the four kinases were determined in the HCT-116 cell line (Table 6). CLK2 was determined to be the most potent with an IC50 value of 15 nM. From the seven kinases that were identified in the biochemical kinase screen, only one additional kinase (PHKG-1) was monitored in the HCT-116 KiNative kinase panel, and PhKG-1 only showed 26% binding in the 3 μM screen. Inhibition of TTK and CLK2 phosphorylation substrates was monitored to confirm the cellular inhibitory mechanism of action. Cal-51 cells were treated with compound 23 for 1 h and analyzed by Western blot using antibodies against the autophosphorylation of TTK at T686 or phosphorylation of SR protein 75, a substrate of CLK2. Quantification of the Western blots enabled IC50 determinations. The p-TTK and p-SRp75 potency of 23 was shown to be 0.057 and 0.549 μM, respectively (Figure 3a). To assess the scope of the TNBC sensitivity versus Luminal BC resistance to compound 23, two additional cell lines were chosen in each category. As seen in Figure 3b, the three TNBC lines are highly sensitive to compound 23 while the three Luminal BC lines are resistant.
Reference: J Med Chem. 2017 Nov 9;60(21):8989-9002. https://doi.org/10.1021/acs.jmedchem.7b01223
In vivo activity:
CC-671 (compound 23) was chosen for in vivo efficacy assessment based on potency, selectivity, slow clearance, and long MRT in both rat and mouse species. The optimal in vivo dosing schedule and finalize the target product profile including route of administration. On the basis of the washout data presented in Figure 5, it is likely that daily dosing would be required. It is plausible that with the TTK mechanism, <24 h exposure could be sufficient to commit cells to apoptosis, although likely longer exposure might be necessary to capture all cycling cells in various phases of mitosis. To investigate this hypothesis, compound 23 was administered iv every 3 days (q3d) or every 7 days (q7d) in a Cal-51 mouse xenograft model (Figure 6). Animals were treated for a minimum of 16 days and tumor growth compared to vehicle control and body weight loss (BWL) were measured on the day following the final day of dosing. Compound 23 demonstrated significant tumor growth inhibition (TGI) ((vehicle – treated/vehicle) × 100%) of 71% at both 10 and 20 mg/kg on a q3d dosing schedule (Figure 6a). The BWL in the 20 mg/kg group was higher than in the 10 mg/kg group (17% vs 5%). In the q7d dosing paradigm, 20 mg/kg was well tolerated without appreciable BWL and compound 23 demonstrated 70% TGI (Figure 6b). Both dosing schedules were better tolerated and more efficacious than Taxotere. Taxotere was administered at maximum tolerated dose (5 mg/kg, q4d). The BWL of Taxotere in this model was significant (20%) and required suspended dosing to allow for recovery. These data suggest that q7d dosing was sufficient to provide significant tumor volume reduction with improved tolerability over a more frequent dosing schedule, and thus an iv route of administration was acceptable. Compound 23 has improved efficacy and better tolerability in the Cal-51 xenograft than Taxotere, the current standard of care for TNBC.
Reference: J Med Chem. 2017 Nov 9;60(21):8989-9002. https://doi.org/10.1021/acs.jmedchem.7b01223
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
60.0 |
117.06 |
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
512.57
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 |
In vitro protocol:
1. Riggs JR, Nagy M, Elsner J, Erdman P, Cashion D, Robinson D, Harris R, Huang D, Tehrani L, Deyanat-Yazdi G, Narla RK, Peng X, Tran T, Barnes L, Miller T, Katz J, Tang Y, Chen M, Moghaddam MF, Bahmanyar S, Pagarigan B, Delker S, LeBrun L, Chamberlain PP, Calabrese A, Canan SS, Leftheris K, Zhu D, Boylan JF. The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen. J Med Chem. 2017 Nov 9;60(21):8989-9002. doi: 10.1021/acs.jmedchem.7b01223. Epub 2017 Oct 27. PMID: 28991472.
In vivo protocol:
1. Riggs JR, Nagy M, Elsner J, Erdman P, Cashion D, Robinson D, Harris R, Huang D, Tehrani L, Deyanat-Yazdi G, Narla RK, Peng X, Tran T, Barnes L, Miller T, Katz J, Tang Y, Chen M, Moghaddam MF, Bahmanyar S, Pagarigan B, Delker S, LeBrun L, Chamberlain PP, Calabrese A, Canan SS, Leftheris K, Zhu D, Boylan JF. The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen. J Med Chem. 2017 Nov 9;60(21):8989-9002. doi: 10.1021/acs.jmedchem.7b01223. Epub 2017 Oct 27. PMID: 28991472.
1: Riggs JR, Nagy M, Elsner J, Erdman P, Cashion D, Robinson D, Harris R, Huang D, Tehrani L, Deyanat-Yazdi G, Narla RK, Peng X, Tran T, Barnes L, Miller T, Katz J, Tang Y, Chen M, Moghaddam MF, Bahmanyar S, Pagarigan B, Delker S, LeBrun L, Chamberlain PP, Calabrese A, Canan SS, Leftheris K, Zhu D, Boylan JF. The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen. J Med Chem. 2017 Nov 9;60(21):8989-9002. doi: 10.1021/acs.jmedchem.7b01223. Epub 2017 Oct 27. PubMed PMID: 28991472.
