Reference Detail

Ref Type

PMID

Authors

D. Weber, R. Lehal, V. Frismantas, J-P. Bourquin, M. Bauer, M. Murone, F. Radtke

Title

Pharmacological activity of CB-103: An oral pan-NOTCH inhibitor with a novel mode of action

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	28

URL

https://www.annalsofoncology.org/article/S0923-7534(20)37828-5/fulltext

Abstract Text

Background: NOTCH signalling is a developmental pathway known to play critical roles during embryonic development as well as for regulation of self-renewing tissues. Aberrant activation of NOTCH signalling leads to deregulation of the self-renewal process resulting in sustained proliferation, invasion and metastasis, all of which are hallmarks of cancer. When the NOTCH pathway is inappropriately activated by genetic lesions (over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations), it becomes a major driver for NOTCH-dependent cancers and resistance to standard of care treatment. Several therapeutic approaches have been utilized to block NOTCH signalling, e.g. a) the use of monoclonal blocking antibodies (mAbs) against NOTCH ligands and receptors and b) the use of small molecule gamma-secretase inhibitors (GSIs). Here we report the pharmacological characterization of CB-103, a first-in-class orally-active small molecule, protein-protein interaction inhibitor of the NOTCH transcriptional activation complex. Methods: Primary pharmacodynamic (PD) studies were conducted to investigate CB-103 in relation to its desired therapeutic effect for treating advanced or metastatic haematological and solid tumour malignancies as NOTCH pathway inhibitor. Regarding the PD effect, in vitro studies demonstrated for CB-103 a dose-dependent decrease in NOTCH signalling activation with a unique mechanism compared to GSIs and mAbs. In a panel of > 120 cell lines of various malignancies CB-103 was active on a subset of 24 cancer cell lines, including different solid tumours (breast, lung, sarcomas), lymphomas and leukaemias. Results: Moreover, CB-103 demonstrated anti-NOTCH activity in the Triple-Negative Breast Cancer HCC1187 cell line, being resistant to GSIs due to a NOTCH2 chromosomal translocation. In addition, CB-103 exhibited anti-tumour efficacy in multiple in vivo models and patients derived xenograft models. Conclusions: Safety pharmacology and toxicology studies have been completed and revealed an excellent non-clinical safety profile of CB-103. A first-in-human Phase I/IIA clinical study in advanced solid tumours and haematological malignancies is under preparation.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References