AMG 925 - CAS 1401033-86-0
Catalog number: 1401033-86-0
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C26H29N7O2
Molecular Weight:
471.55
COA:
Inquire
Targets:
CDK
Description:
AMG-925 is a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
Purity:
>98%
Synonyms:
AMG-925; AMG925
MSDS:
Inquire
InChIKey:
BBUVDDPUURMFOX-UHFFFAOYSA-N
InChI:
InChI=1S/C26H29N7O2/c1-16-2-5-18(6-3-16)33-22-13-27-10-8-19(22)20-12-28-26(31-25(20)33)30-23-7-4-17-14-32(24(35)15-34)11-9-21(17)29-23/h4,7-8,10,12-13,16,18,34H,2-3,5-6,9,11,14-15H2,1H3,(H,28,29,30,31)
Canonical SMILES:
CC1CCC(CC1)N2C3=C(C=CN=C3)C4=CN=C(N=C42)NC5=NC6=C(CN(CC6)C(=O)CO)C=C5
1.Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia.
Keegan K1, Li C, Li Z, Ma J, Ragains M, Coberly S, Hollenback D, Eksterowicz J, Liang L, Weidner M, Huard J, Wang X, Alba G, Orf J, Lo MC, Zhao S, Ngo R, Chen A, Liu L, Carlson T, Quéva C, McGee LR, Medina J, Kamb A, Wickramasinghe D, Dai K. Mol Cancer Ther. 2014 Apr;13(4):880-9. doi: 10.1158/1535-7163.MCT-13-0858. Epub 2014 Feb 13.
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively.
2.Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Li Z1, Wang X, Eksterowicz J, Gribble MW Jr, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo J Med Chem. 2014 Apr 24;57(8):3430-49. doi: 10.1021/jm500118j. Epub 2014 Apr 2.
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
3.AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia.
Li C1, Liu L2, Liang L2, Xia Z2, Li Z2, Wang X2, McGee LR2, Newhall K2, Sinclair A2, Kamb A2, Wickramasinghe D2, Dai K2. Mol Cancer Ther. 2015 Feb;14(2):375-83. doi: 10.1158/1535-7163.MCT-14-0388. Epub 2014 Dec 8.
Resistance to FLT3 inhibitors is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG 925, a dual FLT3/CDK4 inhibitor, has been developed to overcome this resistance. It is hypothesized that the combined inhibition of FLT3 and CDK4 may reduce occurrence of the FLT3 resistance mutations, and thereby prolong clinical responses. To test this hypothesis, we attempted to isolate AML cell clones resistant to AMG 925 or to FLT3 inhibitors. After a selection of over 8 months with AMG 925, we could only isolate partially resistant clones. No new mutations in FLT3 were found, but a 2- to 3-fold increase in total FLT3 protein was detected and believed to contribute to the partial resistance. In contrast, selection with the FLT3 inhibitors sorafenib or AC220 (Quizartinib), led to a resistance and the appearance of a number of mutations in FLT3 kinase domains, including the known hot spot sites D835 and F691. However, when AC220 was combined with the CDK4 inhibitor PD0332991 (palbociclib) at 0.
Molecular Weight Calculator Molarity Calculator Solution Dilution Calculator

Related CDK Products


CAS 1231929-97-7 Abemaciclib

Abemaciclib
(CAS: 1231929-97-7)

Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with poten...

CAS 143621-35-6 Triapine

Triapine
(CAS: 143621-35-6)

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a ribonucleotide reductase inhibitor and iron chelator with anti-tumor activity.

CAS 802539-81-7 Milciclib

Milciclib
(CAS: 802539-81-7)

Milciclib is an orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) and thropomyosin receptor kinase A (TRKA), with potential antineoplastic activi...

CAS 845714-00-3 PHA-767491

PHA-767491
(CAS: 845714-00-3)

PHA-767491 is a potent, ATP-competitive dual cdc7/cdk9 inhibitor (IC50 values are 10 and 34 nM respectively) that prevents initiation of DNA replication.

CAS 571189-11-2 PD 0332991 hydrochloride

PD 0332991 hydrochloride
(CAS: 571189-11-2)

PD 0332991 hydrochloride is a cyclin-dependent kinase (CDK) inhibitor with high affinity for CDK4 and CDK6. It has the potential for breast cancer treatment.

CAS 920113-03-7 Riviciclib HCl

Riviciclib HCl
(CAS: 920113-03-7)

Riviciclib, also known as P276-00, is a novel CDK1, CDK4 and CDK9 inhibitor with IC50 of 79 nM, 63 nM and 20 nM, respectively. P276-00 selectively binds to and ...

THZ2
(CAS: 1604810-84-5)

THZ2, an analog of THZ1, with the potential to treat Triple-negative breast cancer (TNBC), it is a potent and selective CDK7 inhibitor which overcomes the insta...

CAS 784210-87-3 RGB-286638

RGB-286638
(CAS: 784210-87-3)

RGB-286638 is a novel CDK inhibitor. It inhibited several tyrosine and serine/threonine non-CDK enzymes, i.e. GSK-3β, TAK1, AMPK, Jak2, MEK1. It demonstrated eq...

Chemical Structure

CAS 1401033-86-0 AMG 925

Quick Inquiry

Verification code

Featured Items