Delving into the Latest Updates on CEP-1347 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

MAP3K11

Mechanism

MAP3K11 inhibitors(Mitogen-activated protein kinase kinase kinase 11 inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseImmune System Diseases+ [2]

Active Indication-

Inactive Indication

Alzheimer DiseaseAsthmaCognition Disorders+ [2]

Originator Organization

H. Lundbeck A/S

Active Organization-

Inactive Organization

H. Lundbeck A/SKyowa Hakko Kogyo Co., Ltd.

Cephalon, Inc.

+ [1]

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC33H33N3O5S2

InChIKeySCMLRESZJCKCTC-KMYQRJGFSA-N

CAS Registry156177-65-0

Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack of effective therapies. Mixed-lineage protein kinase 3 (MLK3) is a protein that is often upregulated in TNBC and involved in driving the tumorigenic potential of cancer cells. Here, we present a selective MLK3 degrader, CEP1347-VHL-02, based on the pan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel-Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome system in several cell line models but did not degrade other MLK family members. Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC.

01 Sep 2023·European Journal of Medicinal Chemistry

The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies

Review

Author: Recio, Javier ; Moreno, Ricardo ; Gil, Carmen ; Barber, Santiago ; Martinez, Ana

Selective and brain-permeable protein kinase inhibitors are in preclinical development for treating neurodegenerative diseases. Among them, MLK3 inhibitors, with a potent neuroprotective biological action have emerged as valuable agents for the treatment of pathologies such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis. In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment.

30 Aug 2023·Cancers

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells.

Article

Author: Togashi, Keita ; Okada, Masashi ; Mitobe, Yuta ; Kitanaka, Chifumi ; Sonoda, Yukihiko ; Sugai, Asuka ; Nakagawa-Saito, Yurika ; Suzuki, Shuhei

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2-p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

100 Deals associated with CEP-1347

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05403

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 3	CA	Cephalon, Inc.	01 Mar 2002
Parkinson Disease	Phase 3	PR	Cephalon, Inc.	01 Mar 2002
Parkinson Disease	Phase 3	PR	Cephalon, Inc.	01 Mar 2002
Parkinson Disease	Phase 3	PR	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Phase 3	CA	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Phase 3	CA	Cephalon, Inc.	01 Mar 2002
Parkinson Disease	Phase 3	PR	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Phase 3	CA	H. Lundbeck A/S	01 Mar 2002
Asthma	Phase 3	IS	-	-
Asthma	Phase 3	IS	-	-