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.
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.
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.
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.
EUDRACT #2017‐001491‐35
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Cellestia Biotech AG.
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.