Delving into the Latest Updates on AS-602868 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AS 2868, AS 602868, AS-2868

+ [4]

Target

IKKβ x NFKB1

Mechanism

IKKβ inhibitors(inhibitor of nuclear factor kappa B kinase subunit beta inhibitors), NFKB1 modulators(Nuclear factor kappa B modulators)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesOther Diseases+ [2]

Active Indication-

Inactive Indication

Hematologic NeoplasmsInflammationMultiple Sclerosis

Originator Organization

Merck Serono SA

Active Organization-

Inactive Organization

Celgene Corp.Merck Serono SA

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC18H14N4O3S

InChIKeyGZGLPBNOIFLLRE-UHFFFAOYSA-N

CAS Registry219773-55-4

Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis.

METHODS:

Analysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14-28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10(-8)-10(-6) M) and IKK2 (NF-κB) inhibition (AS602868, 0-3 μM (0-3×10(-6) M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay.

RESULTS:

Dexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC.

CONCLUSIONS:

Dexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways.

01 Jun 2014·Bioorganic & medicinal chemistry lettersQ4 · MEDICINE

Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors

Q4 · MEDICINE

Article

Author: Han, Gyoonhee ; Kang, Jong Soon ; Kim, Hyuntae ; Yang, Jee Sun ; Kim, Myung-Hwa ; Joe, Bo-Young ; Lee, Chulho ; Park, Chun-Ho ; Chun, Kwangwoo ; Kim, Hye Yun ; Lee, Jangik I

Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKβ was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

01 Jul 2011·Cancer chemotherapy and pharmacologyQ4 · MEDICINE

Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868

Q4 · MEDICINE

Article

Author: Adriana Plesa ; Emeline Cros-Perrial ; Céline Keime ; Julie A. Vendrell ; Stéphanie Herveau ; Charles Dumontet ; Michel Dreano ; Lars Petter Jordheim ; Delphine Demangel

PURPOSE:

The need for new treatment options for acute myeloid leukemia (AML) is increasing. AS602868 is a novel investigational drug with reported activity on AML cells.

METHODS:

We studied gene expression profiles in AML blasts exposed to AS602868 in order to better understand its mechanism of action. We analyzed the in vitro cytotoxicity of AS602868 alone or in combination with daunorubicin, etoposide or cytarabine. To document AS602868-induced IKK2 inhibition in fresh AML cells, a flow cytometry analysis of IκB was performed. Finally, the effect of AS602868 on gene expression in fresh AML cells was analyzed.

RESULTS:

The results show that AML cells are globally as sensitive to AS602868 as they are to cytarabine, with large interindividual variations. Combinations with conventional antileukemic agents showed enhanced cytotoxic activity in subsets of patients. IKK2 appeared to be effectively inhibited by 100 μM AS602868 in fresh leukemic cells. Gene expression profiling and gene ontology analyses identified several groups of genes induced/inhibited by exposure to AS602868 and/or exhibiting a correlation with sensitivity to this agent in vitro. Of note, the expression of several genes related to immune function was found to be significantly altered after exposure to AS602868.

CONCLUSION:

These data suggest that AS602868 is cytotoxic against fresh human AML blasts and provide insights regarding the mechanisms of cytotoxicity.

100 Deals associated with AS-602868

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Phase 1	US	Merck Serono SA	-
Inflammation	Preclinical	US	-	-
Multiple Sclerosis	Discovery	US	Celgene Corp.	-
Multiple Sclerosis	Discovery	CH	Merck Serono SA	-