Delving into the Latest Updates on CAM-2602 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Aurora A

Mechanism

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

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease

Active Indication

Pancreatic Cancer

Inactive Indication-

Originator Organization

University of Cambridge

Active Organization

University of Cambridge

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Dagostin, Claudio ; Hyvonen, Marko ; Moschetti, Tommaso ; McKenzie, Grahame ; Feng, Tzu-Shean ; Rooney, Timothy P. C. ; Srinivasan, Rajavel ; Scott, Duncan E. ; Rocaboy, Mathieu ; Alcaide, Anna ; Perrior, Trevor R. ; Blundell, Tom L. ; Alza, Esther ; Fischer, Gerhard ; Spring, David R. ; Perrior, Trevor R ; Higueruelo, Alicia ; Stockwell, Simon R. ; Venkitaraman, Ashok R. ; Abell, Chris ; Skidmore, John ; Blaszczyk, Beata ; Rossmann, Maxim ; Guarino, Estrella ; Wang, Xuelu ; Asteian, Alice

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.

100 Deals associated with CAM-2602

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