CCT241736
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MedKoo CAT#: 407950

CAS#: 1402709-93-6

Description: CCT241736 is a potent and orally active and dual FLT3-Aurora inhibitor. CCT241736 has IC50 values against FLT3, Aurora A and Aurora B of 0.035, 0.015 and 0.1 μM respectively. CCT241736 inhibits a wide range of FLT3 mutants, including FLT3-ITD, -D835Y, -D835H, -K663Q and -N841I. In cellular assays, CCT241736 inhibits viability of the human FLT3-ITD positive AML cell lines MOLM-13 and MV-4;11 with EC50 values of 0.1 and 0.27

Chemical Structure

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CCT241736
CAS# 1402709-93-6
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 407950
Name: CCT241736
CAS#: 1402709-93-6
Chemical Formula: C22H23Cl2N7
Exact Mass: 455.14
Molecular Weight: 456.375
Elemental Analysis: C, 57.90; H, 5.08; Cl, 15.54; N, 21.48

Price and Availability

Size Price Availability Quantity
50mg USD 450 2 Weeks
100mg USD 800 2 Weeks
200mg USD 1450 2 Weeks
500mg USD 2850 2 Weeks
1g USD 3950 2 Weeks
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Synonym: CCT241736; CCT-241736; CCT 241736;

IUPAC/Chemical Name: 6-chloro-7-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

InChi Key: AKJBLKUZXRMECW-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H23Cl2N7/c1-14-17(13-29(2)28-14)21-26-19-20(18(24)11-25-22(19)27-21)31-9-7-30(8-10-31)12-15-3-5-16(23)6-4-15/h3-6,11,13H,7-10,12H2,1-2H3,(H,25,26,27)

SMILES Code: CC1=NN(C)C=C1C2=NC3=C(N4CCN(CC5=CC=C(Cl)C=C5)CC4)C(Cl)=CN=C3N2

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

Shelf Life: >3 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: 2934.99.03.00

More Info: M respectively. In vivo, mouse tumor xenograft models of MOLM-13, MV-4;11 and the doubly-mutated cell line, MOLM-13-RES, are also sensitive to CCT241736, with biomarker modulation consistent with dual inhibition of FLT3 and Aurora kinases. In summary, dual inhibition of FLT3 and the critical mitotic kinase Aurora by CCT241736 may represent a novel treatment strategy for FLT3-mutated AML by overcoming the effects of high FL levels and limiting resistance caused by secondary mutations of the FLT3 gene.

Product Data:
Product Data
Instruction:
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Biological target: CCT241736 is a potent and orally bioavailable dual FLT3 and Aurora kinase inhibitor, which inhibits Aurora kinases (Aurora-A Kd, 7.5 nM, IC50, 38 nM; Aurora-B Kd, 48 nM), FLT3 kinase (Kd, 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd, 38 nM) and FLT3(D835Y) (Kd, 14 nM).
In vitro activity: CCT241736 (Compound 27e) is a potent and orally bioavailable dual FLT3 and Aurora kinase inhibitor, which inhibits Aurora kinases (Aurora-A Kd, 7.5 nM, IC50, 38 nM, Aurora-B Kd, 48 nM), FLT3 kinase (Kd, 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd, 38 nM) and FLT3(D835Y) (Kd, 14 nM). CCT241736 exhibits antiproliferative activity in a range of human tumor cell lines, such as HCT116 human colon carcinoma (GI50, 0.300 μM), the human FLT3-ITD positive AML cell lines MOLM-13 (GI50, 0.104 μM) and MV4-11 (GI50, 0.291 μM). CCT241736 also inhibits both the autophosphorylation of Aurora-A at T288 (a biomarker for Aurora-A inhibition: IC50, 0.030 μM) and histone H3 phosphorylation at S10 (a biomarker for Aurora-B inhibition: IC50, 0.148 μM), consistent with potent cellular activity versus both Aurora-A and -B. CCT241736 suppresses Aurora-A in MOLM-13 cells with concomitant inhibition of FLT3 signaling. Reference: J Med Chem. 2012 Oct 25;55(20):8721-34. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23043539/
In vivo activity: Human tumor xenograft experiments (MOLM-13) were carried out in athymic mice to evaluate the efficacy of CCT241736 in vivo. CCT241736 reduced tumor growth compared with that in vehicle-treated mice in a dose-dependent manner with no observed toxicity on chronic dosing (Figure 3A). To analyze the PD activity of CCT241736 in vivo, tumors were collected at 2 hours after the final dose, and the lysates were analyzed by immunoblotting. Reduction of phospho-Aurora-A and phospho-STAT5 indicates inhibition of both Aurora A and FLT3 in a dose-dependent manner (Figure 3B). Similarly, survivin levels were reduced in a dose-dependent manner, which indicates that CCT241736 induced apoptosis in vivo. A confirmatory study in a second in vivo FLT3-ITD+ AML human tumor xenograft model (MV4-11) showed that CCT241736 significantly inhibits the growth of MV4-11 xenografts with clear inhibition of both HH3 and STAT5 phosphorylation at 2 hours after the final dose, indicating a dual inhibition of both Aurora and FLT3 downstream pathways in the tumor.15 To demonstrate that Aurora kinase inhibition by CCT241736 makes a significant contribution to efficacy in FLT3-mutated AML, samples of the MV4-11 tumors from the animals dosed with 100 mg/kg at 2 hours after administration were analyzed by immunofluorescence microscopy. More than one third (36%) of mitotic cells from tumors treated with CCT241736 formed monopolar or abnormal spindles, a typical phenotype for Aurora kinase inhibition.23 In comparison, this phenotype was observed in only 4% of mitotic cells in tumors from mice treated with vehicle control (Figure 3C-D). These data confirm the contribution of Aurora inhibition by CCT241736 to the in vivo efficacy and the already known induced phenotype from previous studies using Aurora inhibitors. Reference: Blood Adv. 2020 Apr 14;4(7):1478-1491. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32282883/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 75.0 164.34

Preparing Stock Solutions

The following data is based on the product molecular weight 456.38 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:
In vitro protocol: 1. Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. J Med Chem. 2012 Oct 25;55(20):8721-34. doi: 10.1021/jm300952s. Epub 2012 Oct 8. PMID: 23043539; PMCID: PMC3483018. 2. Wood FL, Shepherd S, Hayes A, Liu M, Grira K, Mok Y, Atrash B, Faisal A, Bavetsias V, Linardopoulos S, Blagg J, Raynaud FI. Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology species. Eur J Pharm Sci. 2019 Nov 1;139:104899. doi: 10.1016/j.ejps.2019.04.004. Epub 2019 Apr 3. PMID: 30953752; PMCID: PMC6892276.
In vivo protocol: 1. Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. J Med Chem. 2012 Oct 25;55(20):8721-34. doi: 10.1021/jm300952s. Epub 2012 Oct 8. PMID: 23043539; PMCID: PMC3483018. 2. Moore AS, Faisal A, Mak GWY, Miraki-Moud F, Bavetsias V, Valenti M, Box G, Hallsworth A, de Haven Brandon A, Xavier CPR, Stronge R, Pearson ADJ, Blagg J, Raynaud FI, Chopra R, Eccles SA, Taussig DC, Linardopoulos S. Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736. Blood Adv. 2020 Apr 14;4(7):1478-1491. doi: 10.1182/bloodadvances.2019000986. PMID: 32282883; PMCID: PMC7160287.

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http://mct.aacrjournals.org/content/10/11_Supplement/B74