Last update 21 Nov 2024

MZ-1

Last update 21 Nov 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms

BET PROTAC(Boehringer Ingelheim/University of Dundee), Proteolysis targeting chimeric molecules(Boehringer Ingelheim/University of Dundee), SMARC2 protein degader(Boehringer Ingelheim/University of Dundee)

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Target

BRD2 x BRD3 x BRD4

Mechanism

BRD2 inhibitors(Bromodomain-containing protein 2 inhibitors), BRD3 inhibitors(Bromodomain-containing protein 3 inhibitors), BRD4 degraders(Bromodomain-containing protein 4 degraders)

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Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Boehringer Ingelheim GmbH

University Of Dundee

Active Organization

Boehringer Ingelheim RCV GmbH & Co. KG

University Of Dundee

Boehringer Ingelheim GmbH

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC49H60ClN9O8S2

InChIKeyPTAMRJLIOCHJMQ-PYNGZGNASA-N

CAS Registry1797406-69-9

100 Clinical Results associated with MZ-1

100 Translational Medicine associated with MZ-1

100 Patents (Medical) associated with MZ-1

Literatures (Medical) associated with MZ-1

01 Nov 2024·Breast Cancer Research and Treatment

BET-directed PROTACs in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-436

Article

Author: Teufelsbauer, Maryana ; Hamilton, Gerhard ; Eggerstorfer, Marie-Therese ; Hammond, Dennis Clyde ; Stickler, Sandra

AbstractPurposeThis study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.MethodsCytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.ResultsJQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.ConclusionThe degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.

11 Oct 2024·Science Advances

Mechanism of degrader-targeted protein ubiquitinability

Article

Author: Hay, Ronald T. ; Nakasone, Mark A. ; Sathe, Gajanan ; Crowe, Charlotte ; Craigon, Conner ; Makukhin, Nikolai ; Ciulli, Alessio ; Tatham, Michael H. ; Chandler, Sarah

Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 BD2 toward UBE2R1-ubiquitin, and Lys 456 at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4 BD2 , with cellular degradation and ubiquitinomics confirming the importance of Lys 456 and nearby Lys 368 /Lys 445 , identifying the “ubiquitination zone.” Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 BD2 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.

01 Mar 2024·Anticancer Research

BRD4-targeting PROTACs Synergize With Chemotherapeutics Against Osteosarcoma Cell Lines

Article

Author: Teufelsbauer, Maryana ; Lang, Clemens ; Hohenegger, Martin ; Stickler, Sandra ; Rath, Barbara ; Hamilton, Gerhard ; Weigl, Lukas

BACKGROUND/AIMOsteosarcoma at an advanced stage has a poor outcome, and novel targeted therapies are needed, especially for metastatic disease. Bromodomain inhibitors (BETi) are epigenetic modulators that broadly impair the expression of oncogenic proteins and exert antitumor effects. BETi can be combined with chemotherapeutics to increase therapeutic responses with superior effects in the form of proteolysis targeting chimeras (PROTACs) that degrade proteins of interest (POI) in multiple cycles. This work aimed to investigate the efficacy of BETi, such as JQ1, dBET57, and MZ1 PROTACs in combination with cytotoxic drugs against osteosarcoma cell lines.MATERIALS AND METHODSChemosensitivity of the osteosarcoma cell lines HOS, Saos-2, MG-63, and G292 were tested with BET-directed agents alone or in combination with cytotoxic drugs comprising cisplatin, doxorubicin, topotecan, and gemcitabine using cell viability assays.RESULTSThe BET degraders exhibited highest toxicity to HOS cells and showed synergistic activity in combination with the chemotherapeutics, except for the degrader - topotecan/gemcitabine combinations. Highest synergy between BET agents and chemotherapeutics were found for the more chemoresistant Saos-2 cells and potentiation of toxicity in MG-63 cells for the BET agents - doxorubicin combinations and the MZ1-topotecan pair. HOS and Saos-2 cell lines had reduced protein expression of AXL, BCL-X, e-cadherin, CAIX, EpCAM, ErbB2, and vimentin in response to JQ1, MZ1, and BET57.CONCLUSIONThe study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials.

100 Deals associated with MZ-1

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	DE	Boehringer Ingelheim GmbH	-

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MZ-1

Overview

Basic Info

Structure

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R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation