CCT245737 (SRA737)

Catalog No.S8253 Batch:S825302

Technical Data

Formula	C₁₆H₁₆F₃N₇O
Molecular Weight	379.34	CAS No.	1489389-18-5
Solubility (25°C)*	In vitro	DMSO	76 mg/mL (200.34 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

CCT245737 (SRA737) is an orally active CHK1 inhibitor with The IC50 of 1.4 nM. It exhibits >1,000-fold selectivity against CHK2 and CDK1.

Targets

Chk1 ^[1]
(Cell-free assay)

1.4 nM

In vitro

CCT245737 is a potent inhibitor of recombinant human CHK1 with IC50 of 1.4±0.3 nM (mean±SD, n = 3, EZ Reader II assay). There is > 1,000-fold selectivity for CHK1 versus the functionally important kinases CDK1 and CHK2 (IC50=1.26-2.44 and 9.03 μM, respectively), and at least a 90-fold selectivity against cross-reacting kinases such as ERK8, PKD1, RSK1 and 2. CCT245737 potently inhibits cellular CHK1 activity (IC50 30-220nM) and enhances SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. It can abrogate an induced G2/M arrest. CCT245737 has high cell permeability, as measured by transport across a CaCo2 cell monolayer^[1].

In vivo

Mouse oral bioavailability is complete (100%) with extensive tumor exposure. CCT245737 shows significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. An i.v. dose of 10mg/kg CCT245737 into BALB/c mice gives a peak plasma concentration of 4μmol/L, with a half-life of 2.86h, an AUC0-∞ of 9.96μmol.h/L, a plasma clearance of 2.1L/h/kg and a large volume of distribution (0.19L). The equivalent oral dose gave an almost identical profile with an AUC0-∞ of 10.4μmol.h/L showing complete oral bioavailability (F = 105%). In a word, CCT245737 shows complete oral bioavailability with linear pharmacokinetics and high tumor/plasma ratios consistent with extensive tumor exposure. Adequate CCT245737 tumor drug exposure takes a significant antitumor activity^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines The colon tumor cell lines HT29 and SW620, the pancreatic cancer cell line MiaPaCa-2 and the non-small cell lung cancer Calu6 cell line Concentrations -- Incubation Time 96 h Method Cytotoxicity is determined as the drug concentration that gave 50% inhibition of tumor cell proliferation (GI50) using a 96h (i.e. 4-doublings) Sulforhodamine B (SRB) assay. Inhibition of intracellular CHK1 activity is measured using a cell based ELISA for the abrogation of an induced G2 checkpoint (mitosis induction assay, MIA).
Animal Study:^{^[1]}	Animal Models BALB/c mice Dosages 10mg/kg(i.v.); 150mg/kg(p.o.) Administration i.v. or p.o. administration

Cell Assay:^{^[1]}

Cell lines
The colon tumor cell lines HT29 and SW620, the pancreatic cancer cell line MiaPaCa-2 and the non-small cell lung cancer Calu6 cell line
Concentrations
--
Incubation Time
96 h
Method
Cytotoxicity is determined as the drug concentration that gave 50% inhibition of tumor cell proliferation (GI50) using a 96h (i.e. 4-doublings) Sulforhodamine B (SRB) assay. Inhibition of intracellular CHK1 activity is measured using a cell based ELISA for the abrogation of an induced G2 checkpoint (mitosis induction assay, MIA).

Animal Study:^{^[1]}

Animal Models
BALB/c mice
Dosages
10mg/kg(i.v.); 150mg/kg(p.o.)
Administration
i.v. or p.o. administration

References

[1] Walton MI, et al. Oncotarget. 2016, 7(3):2329-42.

Selleck's CCT245737 (SRA737) has been cited by 8 publications

Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas [ bioRxiv, 2024, 2024.05.03.592420]	PubMed: 38766189
Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 [ Mol Oncol, 2023, 10.1002/1878-0261.13537]	PubMed: 37866880
Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway [ Biochem J, 2022, 479(19):2063-2086]	PubMed: 36240066
Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma [ Mol Cancer, 2021, 20(1):97]	PubMed: 34315482
CHK1 inhibition exacerbates replication stress induced by IGF blockade [ Oncogene, 2021, 10.1038/s41388-021-02080-1]	PubMed: 34773074
Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death [ Cancer Discov, 2020, CD-20-0581]	PubMed: 32988961
Small Molecule Inhibitors and a Kinase-Dead Expressing Mouse Model Demonstrate That the Kinase Activity of Chk1 Is Essential for Mouse Embryos and Cancer Cells [ Life Sci Alliance, 2020, 3(8):e202000671]	PubMed: 32571801
Checkpoint kinase-1 inhibition and etoposide exhibit a strong synergistic anticancer effect on chronic myeloid leukemia cell line K562 by impairing homologous recombination DNA damage repair [ Oncol Rep, 2020, 44(5):2152-2164]	PubMed: 32901871

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SHIPPING AND STORAGE
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