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66P - Pharmacological activity of CB-103: An oral pan-NOTCH inhibitor targeting the NOTCH transcription complex

Presentation Number
66P
Lecture Time
17:10 - 17:10
Speakers
  • Dirk Weber (Basel, CH)
Session Name
Location
Foyer La Scene, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
17:10 - 18:00
Authors
  • Dirk Weber (Basel, CH)
  • Rajwinder Lehal (Basel, CH)
  • Viktoras Frismantas (Zürich, CH)
  • Jean-Pierre Bourquin (Zürich, CH)
  • Michael Bauer (Basel, CH)
  • Maximilien Murone (Basel, CH)
  • Freddy Radtke (Lausanne, CH)

Abstract

Background

NOTCH signalling is a key development pathway whose aberrant activation is known to play a role in multiple human cancers. When the NOTCH pathway is activated by genetic lesions (over expression of ligands/receptors, GOF mutations in receptors, chromosomal translocations), it becomes a major oncogenic driver for NOTCH-dependent cancers and resistance to standard of care treatment.

Methods

So far, two therapeutic approaches have been attempted to block NOTCH signalling in the clinics: (i) using monoclonal antibodies (mAbs) against NOTCH ligands/receptors and (ii) small molecule gamma-secretase inhibitors (GSIs). Clinical activity of these agents was observed, but exposures were usually limited due to various toxicities. To inhibit pan-NOTCH signalling in human tumors independently of the mechanisms of NOTCH activation, and most downstream of the pathway, we have previously reported the discovery of a new class of small molecules protein-protein interaction (PPI) inhibitors able to target assembly of the NOTCH transcription complex, and downregulate expression of NOTCH target genes (e.g. c-MYC, CCND). Here we report the pharmacological characterization of CB-103, a first-in-class oral small molecule, PPI inhibitor of the NOTCH transcription complex.

Results

In vitro studies demonstrated that CB-103 triggers a dose-dependent downregulation in NOTCH signalling with a unique mechanism of action. CB-103 was active in a subset of cancer cell lines from various malignancies, including different solid tumour indications, lymphomas and leukaemias. Moreover, CB-103 demonstrated anti-tumour efficacy in the Triple-Negative Breast Cancer HCC1187 model, resistant to GSIs due to NOTCH2 chromosomal translocation, and in multiple in vivo models of NOTCH-driven T-ALL (cell lines and patients derived xenograft), as single agent or in combination with various anticancer drugs.

Conclusions

Safety pharmacology and toxicology studies have been completed and revealed an excellent non-clinical safety profile of CB-103. Clinical development of CB-103 with a first-in-human Phase I/IIA clinical study in solid tumours and haematological malignancies has been started in Spain, Netherlands and Switzerland.

Clinical trial identification

EUDRACT #2017‐001491‐35

Legal entity responsible for the study

Cellestia Biotech AG Hochbergerstrasse 60C CH-4057 Basel Switzerland

Funding

Cellestia Biotech AG.

Disclosure

D. Weber: Employee (CMO) and shareholder of Cellestia. R. Lehal: Employee (CSO) and shareholder of Cellestia. J-P. Bourquin: Member of Medical Advisory Board Cellestia. M. Bauer: Employee (CEO) and shareholder of Cellestia. M. Murone: Employee (COO) and shareholder Cellestia. F. Radtke: Chairman of the Board and shareholder of Cellestia. All other authors have declared no conflicts of interest.

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