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602306-29-6 (AZD-5438)

1

Identification

AZD-5438 AZD-5438
Name AZD-5438
Formula C18H21N5O2S
MW 371.46
CAS No. 602306-29-6
EINECS
Smiles O=S(C1=CC=C(NC2=NC(C3=CN=C(N3C(C)C)C)=CC=N2)C=C1)(C)=O
Synonyms AZD 5438;AZD5438; 4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-N-(4-(methylsulfonyl)phenyl)pyrimidin-2-amine
InChI InChI=1S/C18H21N5O2S/c1-12(2)23-13(3)20-11-17(23)16-9-10-19-18(22-16)21-14-5-7-15(8-6-14)26(4,24)25/h5-12H,1-4H3,(H,19,21,22)
2

Introduction

AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM.

Background Information

AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2-1.7 μM), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. AZD5438 blocks cell cycling at G2-M, S and G1 phases; reduces the proportion of actively cycling cells in vivo. The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers. ......by AbMole BioScience
AZD5438 is a potent inhibitor of cyclin-dependent kinase (CDK) 1, 2 and 9 (IC50 values are 16, 6 and 20 nM respectively). ......by AdooQ BioScience, LLC
AZD 5438 is an antiproliferative agent and potent inhibitor of cyclin-dependent kinases Cdk1/cyclin B1 (IC50 = 16 nM), Cdk2/cyclin E (IC50 = 6 nM), Cdk2/cyclin A (IC50 = 45 nM), Cdk6/cyclin D3 (IC50 = 21 nM), and Cdk9/cyclin T (IC50 = 20 nM). AZD5438 also inhibits the kinase activity of p25-cdk5 (IC50 = 14 nM) and glycogen synthase kinase 3β (IC50 = 17 nM). ......by Affix Scientific
Description ......by Apexbio Technology LLC
AZD5438 is a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC(50), 16, 6, and 20 nmol/L, respectively). Broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has t ......by BOC Sciences
AZD-5438 is a potent inhibitor of cyclin-dependent kinases (CDKs) (IC₅₀ values are 16, 6 and 20 nM for CDK1, 2, and 9, respectively). Displays antiproliferative activity in human tumor cell lines. It is less potent to CDK5/6 and also inhibits GSK3β. ......by BioVision, Inc.,
AZD-5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM in cell-free assays. It also inhibits GSK3β, but is less potent to CDK5/6. ......by MedChemexpress Co., Ltd.
AZD5438 is a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC(50), 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC(50) range, 0.2-1.7 micromol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G(2)-M, S, and G(1) phases. ......by MedKoo Biosciences, Inc.
A potent and oral inhibitor of CDK1/2/9 with IC50 of 16/6/20 nM, respectively; also inhibits the kinase activity of p25-Cdk5 (IC50=14 nM) and GSK-3β (IC50=17 nM) in vitro, displays 75-fold less active against cyclin D-Cdk4; shows significant antiproliferative activity in human tumor cell lines (IC50 range: 0.2-1.7 uM), inhibits the phosphorylation of Cdk substrates pRb, nucleolin, PP1A, and RNA polymerase II COOH-terminal domain and blocks cell cycle; inhibits the human tumor xenograft growth in vivo; also inhibits PASTA kinase in L. monocytogenes (PrkA) and L. monocytogenes growth in a β-lactam-synergism-dependent manner.Solid TumorsPhase 1 Discontinued ......by ProbeChem
AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM in cell-free assays. It is less potent to CDK5/6 and also inhibits GSK3β. Phase 1. ......by Selleck Chemicals LLC
AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM in cell-free assays. It is less potent to CDK5/6 and also inhibits GSK3β. Phase 1. ......by Target Molecule Corp.
Potent inhibitor of cyclin-dependent kinase (cdk) 1, 2 and 9 (IC50 values are 16, 6 and 20 nM respectively). Exhibits antiproliferative activity in human tumor cell lines. Blocks cell cycling at G2-M, S and G1 phases; reduces the proportion of actively cycling cells in vivo. ......by Tocris Bioscience Inc.
3

Protocol(Only for Reference)

Cell Experiment

Cell lines MCF-7, HCT-116, A549, and IM-9
Conditions 0 to 10 μM; 48 hours or 72 hours
Method AZD5438 is tested against solid tumor cell lines. Briefly, cells are incubated for 48 hours with AZD5438 at a range of concentrations. At the end of incubation, the cells are pulsed with 5-bromo-2′-deoxyuridine (BrdUrd) and the amount of DNA synthesis is measured. The IC50 for inhibition of proliferation is specifically determined independently of cell death. Multiple myeloma cell lines are seeded into 96-well plates in RPMI 1640 supplemented with 10% FCS and glutamine and dosed with AZD5438 for 72 hours. Cell growth is measured using AlamarBlue and GI50 values are calculated with reference to pretreatment control values.
Source Selleck Chemicals LLC

Animal Experiment

Animal Models MCF-7, HCT-116, A549, and IM-9 cells are injected s.c. into the Swiss nude mice and nude rats.
Dosage ≤100 mg/kg
Formulation AZD5438 is dissolved in hydroxy-propyl-methyl-cellulose.
Administration Administered via p.o.
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:White to off-white solid EBNumber:EB000029142

Storage condition

Up to one week at 4°C or six months at -20°C. by Affix Scientific
Desiccate at RT by Tocris Bioscience Inc.

Solubility

DMSO ≥71 mg/mL Water <1.2 mg/mL Ethanol ≥71 mg/mL by MedChemexpress Co., Ltd.
(25°C) * In vitro DMSO 74 mg/mL (199.21 mM); Ethanol74 mg/mL (199.21 mM); Water<1 mg/mL (<1 mM) by Selleck Chemicals LLC
Soluble to 100 mM in DMSO by Tocris Bioscience Inc.
5

Mechanism and Indication

Signaling Pathways Cell Cycle/DNA Damage
Target CDK
Research Area Cancer
Indications
6

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
AZD-5438 - Discontinued
AZD-5438 - Phase 1
7

Safety Data of AZD-5438

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
AbMole BioScience USA
AdooQ BioScience, LLC USA
Affix Scientific 100mg/USD995(In stock);250mg/USD1550(In stock) USA
Apexbio Technology LLC USA
Ark Pharm, Inc. USA
BLD Pharmatech
BOC Sciences
BioVision, Inc., USA
Biochempartner Co., Ltd China
CHEMSCENE, LLC 10mg/USD72();50mg/USD216() USA
Cayman Chemical Company USA
Excenen Pharmatech Co., Ltd. China
MedChemexpress Co., Ltd. 10mg/USD72();50mg/USD216() USA
MedKoo Biosciences, Inc. USA
ProbeChem
Selleck Chemicals LLC 10mg/USD150(In stock);10mM/1mLIn DMSO/USD195(In stock);50mg/USD570(In stock);200mg/USD1670(In stock) USA
Shanghai Haoyuan Chemexpress Co., Ltd. 10mg/USD72();50mg/USD216() China
Target Molecule Corp. 10mg/USD114();50mg/USD198() USA
Tocris Bioscience Inc. USA
10

Related Products

Other Forms of 602306-29-6

Name CAS No Formula MW
JNJ-17203212 821768-06-3 C17H15F6N5O 419.32
DM1-SMe 138148-68-2 C36H50ClN3O10S2 784.38
ML247 1222374-44-8 C18H24N4O3S 376.47
Tubercidin 69-33-0 C11H14N4O4 266.25
Timegadine 71079-19-1 C20H23N5S 365.5
Bamaluzole 87034-87-5 C14H12ClN3O 273.72
Cholest-4-en-3-one, oxime, (3E)- 66538-08-7 C27H45NO 399.65
Bevenopran 676500-67-7 C20H26N4O4 386.44
Vibunazole 80456-55-9 C15H20ClN3O2 309.79
Pparδ agonist 2 870884-12-1 C20H18F3N3O3S 437.44

Recommended Compounds in CDK

Name CAS No Formula MW
LY2857785 1619903-54-6 C26H36N6O 448.6
THZ2 1604810-84-5 C31H28ClN7O2 566.0527
Palbociclib (isethionate) 827022-33-3 C26H35N7O6S 573.66
CDK9-IN-6 1391855-95-0 C27H37ClN6O2 513.07468
ML167 1285702-20-6 C19H17N3O3 335.36
AMG 925 1401033-86-0 C26H29N7O2 471.55
LDC000067 1073485-20-7 C18H18N4O3S 370.43
LEE011 (succinate hydrate) 1374639-79-8 C27H38N8O6X 570.64
LEE011 (succinate) 1374639-75-4 C27H36N8O5 552.63
LEE011 (hydrochloride) 1211443-80-9 C23H31ClN8O 471.0
LEE011 1211441-98-3 C23H30N8O 434.54
WHI-P180 (hydrochloride) 153437-55-9 C16H16ClN3O3 333.77
Wogonin 632-85-9 C16H12O5 284.26
1-NM-PP1 221244-14-0 C20H21N5 331.41
WHI-P180 211555-08-7 C16H15N3O3 297.31
THZ1 1604810-83-4 C31H28ClN7O2 566.05
Senexin A 1366002-50-7 C17H14N4 274.32
CDK4-IN-1 1256963-02-6 C22H29ClN8 440.97
Palbociclib (hydrochloride) 827022-32-2 C24H30ClN7O2 483.99
Purvalanol B 212844-54-7 C20H25ClN6O3 432.9

Recommended Compounds in Same Indication

Name CAS No Formula MW
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Route of Synthesis

12

References

[1]. Camidge, D. Ross; Pemberton, Mike; Growcott, Jim; A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers. Cancer Chemotherapy and Pharmacology (2007), 60(4), 479-488.

[2]. Camidge, D. Ross; Smethurst, Dominic; A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers. Cancer Chemotherapy and Pharmacology (2007), 60(3), 391-398.

[3]. Raghavan P, Tumati V, Yu L, Chan N, Tomimatsu N, Burma S, Bristow RG, Saha D.AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells.Int J Radiat Oncol Biol Phys. 2012 Jul 12.

[4]. Boss DS, Schwartz GK, Middleton MR, Amakye DD, Swaisland H, Midgley RS, Ranson M, Danson S, Calvert H, Plummer R, Morris C, Carvajal RD, Chirieac LR, Schellens JH, Shapiro GI.Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours.Ann Oncol. 2010 Apr;21(4):884-94. Epub 2009 Oct 13.

[5]. Byth KF, Thomas A, Hughes G, Forder C, McGregor A, Geh C, Oakes S, Green C, Walker M, Newcombe N, Green S, Growcott J, Barker A, Wilkinson RW.AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts.Mol Cancer Ther. 2009 Jul;8(7):1856-66. Epub 2009 Jun 9.

Protocol Reference

Byth et al (2009) AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2 and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol.Cancer Ther. 8 1856. PMID: 19509270.

......by Tocris Bioscience Inc.
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More Information

AZD-5438

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