Delving into the Latest Updates on CEP-1347 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

3,9-bis[(ethylthio)methyl]-K-252a

+ [1]

Target

MAP3K11

Action

inhibitors

Mechanism

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

Therapeutic Areas

Nervous System Diseases

Active Indication

Nervous System Diseases

Inactive Indication

Alzheimer DiseaseAsthmaCognition Disorders+ [1]

Originator Organization

H. Lundbeck A/S

Active Organization

Kyowa Hakko Kogyo Co., Ltd.

Inactive Organization

H. Lundbeck A/S

Cephalon, Inc.

deCODE Genetics ehf

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

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.

19 Jul 2024·Oncogene

MLK3 promotes prooncogenic signaling in hepatocellular carcinoma via TGFβ pathway

Article

Author: Viswakarma, Navin ; Rana, Ajay ; Vishnoi, Kanchan ; Wang, Xiaowei ; Kumar, Sandeep ; Srivastava, Piush ; Ke, Rong ; Rana, Basabi ; Srivastava, Deepti ; Singh, Sunil Kumar ; Kashyap, Tanushree ; Maienschein-Cline, Mark ; Nair, Rakesh Sathish ; Menhart, Mary

Advanced hepatocellular carcinoma (HCC) is a lethal disease, with limited therapeutic options. Mixed Lineage Kinase 3 (MLK3) is a key regulator of liver diseases, although its role in HCC remains unclear. Analysis of TCGA databases suggested elevated MAP3K11 (MLK3 gene) expression, and TMA studies showed higher MLK3 activation in human HCCs. To understand MLK3's role in HCC, we utlized carcinogen-induced HCC model and compared between wild-type and MLK3 knockout (MLK3^-/-) mice. Our studies showed that MLK3 kinase activity is upregulated in HCC, and MLK3 deficiency alleviates HCC progression. MLK3 deficiency reduced proliferation in vivo and MLK3 inhibition reduced proliferation and colony formation in vitro. To obtain further insight into the mechanism and identify newer targets mediating MLK3-induced HCCs, RNA-sequencing analysis was performed. These showed that MLK3 deficiency modulates various gene signatures, including EMT, and reduces TGFB1&2 expressions. HCC cells overexpressing MLK3 promoted EMT via autocrine TGFβ signaling. Moreover, MLK3 deficiency attenuated activated hepatic stellate cell (HSC) signature, which is increased in wild-type. Interestingly, MLK3 promotes HSC activation via paracrine TGFβ signaling. These findings reveal TGFβ playing a key role at different steps of HCC, downstream of MLK3, implying MLK3-TGFβ axis to be an ideal drug target for advanced HCC management.

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.

100 Deals associated with CEP-1347

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05403

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 2	Puerto Rico	Cephalon, Inc.	01 Mar 2002
Parkinson Disease	Phase 2	Puerto Rico	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Phase 2	Canada	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Phase 2	Canada	Cephalon, Inc.	01 Mar 2002
Asthma	Phase 2	Iceland	-	-
Parkinson Disease	Discovery	Canada	Cephalon, Inc.	01 Mar 2002
Parkinson Disease	Discovery	Canada	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Discovery	Puerto Rico	H. Lundbeck A/S	01 Mar 2002
Parkinson Disease	Discovery	Puerto Rico	Cephalon, Inc.	01 Mar 2002
Asthma	Discovery	Iceland	-	-