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Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms

Target

Aurora A

Action

inhibitors

Mechanism

Aurora A inhibitors(Serine/threonine-protein kinase Aurora-A inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Julius-Maximilians-Universität Würzburg

Active Organization

Julius-Maximilians-Universität Würzburg

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC46H40ClFN8O10

InChIKeyCNOAPBMMLZMAAH-UHFFFAOYSA-N

CAS Registry2567930-99-6

Author: Knapp, Stefan ; Hofstetter, Julia ; Wanior, Marek ; Dudvarski Stankovic, Nevenka ; Heinzlmeir, Stephanie ; Vogt, Markus ; Baluapuri, Apoorva ; Sotriffer, Christoph ; Schönemann, Lars ; Adhikari, Bikash ; Bozilovic, Jelena ; Schröder, Martin ; Schlosser, Andreas ; Narain, Ashwin ; Bhandare, Pranjali ; Eing, Lorenz ; Diebold, Mathias ; Schwarz, Jessica Denise ; Wolf, Elmar ; Kuster, Bernhard

The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (for example, thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition, we found that the degrader complex was stabilized by cooperative binding between AURORA-A and CEREBLON. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant apoptosis in cancer cell lines and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in cancer.

100 Deals associated with JB171

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