Delving into the Latest Updates on MRT3-007 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CDK5

Mechanism

CDK5 inhibitors(Cyclin-dependent kinase 5 inhibitors)

Therapeutic Areas

NeoplasmsOther Diseases

Active Indication

Pheochromocytoma

Inactive Indication-

Originator Organization

ManRos Therapeutics SA

Active Organization

St. Vincent's Institute of Medical Research

University of Florida

The University of Alabama at Birmingham

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Totenhagen, John ; Reddy, Sushanth ; Meijer, Laurent ; Hatch, Heather ; Ovens, Ashley J ; Bibb, James A ; Guo, Ailan ; Pacak, Karel ; Oakhill, Jonathan S ; Elie, Jonathan ; Telange, Rahul ; Neuzil, Jiri ; Sobh, Amin ; Carter, Angela M ; Strange, Keehn ; Wiederhold, Thorsten ; Sonawane, Yogesh A ; Tan, Chunfeng ; Natarajan, Amarnath ; Gupta, Priyanka ; Ghayee, Hans K

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca²⁺]_i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.

100 Deals associated with MRT3-007

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pheochromocytoma	Preclinical	US	University of Florida	-
Pheochromocytoma	Preclinical	AU	St. Vincent's Institute of Medical Research	-
Pheochromocytoma	Preclinical	US	The University of Alabama at Birmingham	-