Delving into the Latest Updates on HLB-0532259 with Synapse

Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms-

Target

Aurora A x N-Myc

Action

degraders

Mechanism

Aurora A degraders(Serine/threonine-protein kinase Aurora-A degraders), N-Myc degraders(MYCN proto-oncogene, bHLH transcription factor degraders)

Therapeutic Areas

NeoplasmsOther Diseases

Active Indication

Neuroblastoma

Inactive Indication-

Originator Organization

University of Minnesota

Active Organization

University of Minnesota

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Moorthy, Ramkumar ; Levy, Michaella J ; Demir, Özlem ; Gupta, Harshita B ; Aihara, Hideki ; Grillo, Michael J ; Hirsch, Laura E ; Naumann, Jordan A ; Jones, Katherine F M ; Shi, Ke ; Haefner, Ella S ; Harki, Daniel A ; Tang, Jian ; Harris, Reuben S ; Baker, Zachary D ; Amaro, Rommie E ; Levinson, Nicholas M

The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting "undruggable" proteins that are reliant on accessory proteins for cellular stabilization.

100 Deals associated with HLB-0532259

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