CCT244747
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MedKoo CAT#: 406340

CAS#: 1404095-34-6

Description: CCT244747 is a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor with potential anticancer activity. CCT244747 inhibited cellular CHK1 activity (IC(50) 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G(2) arrest in multiple tumor cell lines. CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies.

Chemical Structure

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CCT244747
CAS# 1404095-34-6
Instruction

Theoretical Analysis

MedKoo Cat#: 406340
Name: CCT244747
CAS#: 1404095-34-6
Chemical Formula: C20H24N8O2
Exact Mass: 408.20
Molecular Weight: 408.460
Elemental Analysis: C, 58.81; H, 5.92; N, 27.43; O, 7.83

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 450 Ready to ship
50mg USD 750 Ready to ship
100mg USD 1050 Ready to ship
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Synonym: CCT244747; CCT-244747; CCT 244747.

IUPAC/Chemical Name: (R)-3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile

InChi Key: IENLGMOXAQMNEH-CYBMUJFWSA-N

InChi Code: InChI=1S/C20H24N8O2/c1-13(11-27(2)3)30-20-16(7-21)22-10-19(26-20)25-18-6-17(29-5)15(9-23-18)14-8-24-28(4)12-14/h6,8-10,12-13H,11H2,1-5H3,(H,23,25,26)/t13-/m1/s1

SMILES Code: N#CC1=NC=C(N=C1O[C@@H](CN(C)C)C)NC2=NC=C(C(OC)=C2)C3=CN(N=C3)C

Appearance: Yellow solid powder

Purity: >99% (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 soluble 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: CCT244747 is a CHK1 inhibitor, with an IC50 of 7.7 nM; CCT244747 also abrogates G2 checkpoint with an IC50 of 29 nM.
In vitro activity: Figure 2A shows that SN38 induced S296 CHK1 autophosphorylation in HT29 cells after 24h and this was inhibited by combination with CCT244747 at ≥0.05μM with complete loss of signal at ≥0.5μM. Phosphorylation on S317 and S345 was markedly increased by SN38 exposure and these increases were reversed at ≥0.1μM. However, neither phosphorylation was completely abolished by up to 5μM CCT244747. Phosphorylation of the cell cycle marker pY15 CDK1 was induced by SN38 treatment and this was substantially inhibited by combination with ≥0.5μM CCT244747. The inhibition of CHK1 autophosphorylation and CDK1 phosphorylation coincided with the induction of γH2AX (pS139 H2AX) and PARP cleavage, markers of DNA damage and apoptosis, respectively. Similar results were obtained with gemcitabine and CCT244747 combinations in SW620 cells (Figure 2B), although SW620 cells may be slightly less sensitive than HT29 to CHK1 inhibition. Consequently, these results clearly demonstrate that CCT244747 can inhibit SN38 and gemcitabine-induced CHK1 activity in tumor cells and this correlates with abrogation of cell cycle arrest, induction of DNA damage and apoptosis. Reference: Clin Cancer Res. 2012 Oct 15; 18(20): 5650–5661. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474704/
In vivo activity: The ability of 20 and 26 (CCT244747) to inhibit DNA damaging agent-induced CHK1 signaling in human tumors xenografts in athymic mice after oral dosing was assessed (Figure 3). Activation of the DNA damage response resulting from gemcitabine treatment was shown by the increase in phospho-S317 CHK1 and was sustained over 12 h. CHK1 autophosphorylation on S296 was also seen at both time points in response to gemcitabine treatment. Both 20 and 26 at their MTDs strongly inhibited CHK1 S296 autophosphorylation at 6 h following gemcitabine treatment. Compound 26 continued to show robust inhibition of CHK1 at the 12 h time point, while a less powerful effect was seen for 20 (Figure 3A). Analysis of the drug levels in plasma and tumors showed micromolar plasma concentrations and high distribution to tumor for both compounds (Figure B). The 2-fold higher dose of 26 was associated with an increased exposure compared to 20, as expected. Reference: J Med Chem. 2012 Nov 26; 55(22): 10229–10240. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506129/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.0 122.41

Preparing Stock Solutions

The following data is based on the product molecular weight 408.46 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. Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, Collins I. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40. doi: 10.1021/jm3012933. Epub 2012 Oct 19. PMID: 23082860; PMCID: PMC3506129. 2. Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, Garrett MD. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61. doi: 10.1158/1078-0432.CCR-12-1322. Epub 2012 Aug 28. PMID: 22929806; PMCID: PMC3474704.
In vitro protocol: 1. Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, Collins I. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40. doi: 10.1021/jm3012933. Epub 2012 Oct 19. PMID: 23082860; PMCID: PMC3506129. 2. Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, Garrett MD. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61. doi: 10.1158/1078-0432.CCR-12-1322. Epub 2012 Aug 28. PMID: 22929806; PMCID: PMC3474704.
In vivo protocol: 1. Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, Collins I. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40. doi: 10.1021/jm3012933. Epub 2012 Oct 19. PMID: 23082860; PMCID: PMC3506129. 2. Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, Garrett MD. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61. doi: 10.1158/1078-0432.CCR-12-1322. Epub 2012 Aug 28. PMID: 22929806; PMCID: PMC3474704.

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1: Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, Collins I. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40. doi: 10.1021/jm3012933. Epub 2012 Oct 19. PubMed PMID: 23082860; PubMed Central PMCID: PMC3506129.

2: Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, Garrett MD. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61. doi: 10.1158/1078-0432.CCR-12-1322. Epub 2012 Aug 28. PubMed PMID: 22929806; PubMed Central PMCID: PMC3474704.