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

Abstract

Background: NOTCH signalling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of selfrenewing tissues. Aberrant activation of NOTCH signalling leads to deregulation of the self‐renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, 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. Over 250'000 patients are annually diagnosed with NOTCH dependent cancers, with no specific therapy available to date. Aims: Given the importance of NOTCH signalling in human cancers, several therapeutic approaches have been utilized to block NOTCH signalling. Two of these strategies are; a) the use of monoclonal blocking antibodies (mAbs) against NOTCH ligands and receptors and b) the use of small molecule gamma‐secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full‐length ligand or receptor molecules. As validation of NOTCH as a therapeutic target, clinical activity of these in clinical studies were was observed in various trials for some of these inhibitors (mAbs, GSIs), but treatment and exposure were usually limited due to toxicities, mainly related to gastro‐intestinal adverse events. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations or specific NOTCH mutations, the use of mAbs and GSIs will have very limited clinical benefits. Cellestia has decided to follow a disruptive approach, by blocking NOTCH signalling in the most downstream part of the NOTCH cascade, at the level of the NOTCH transcriptional activation complex, using small molecule inhibitors. Methods: Here we report the pharmacological characterization of CB‐103, a first‐in‐class orally‐active small molecule inhibitor of the NOTCH transcriptional activation complex. Results: We demonstrate that in vitro CB‐103 potently inhibits NOTCH signalling in various leukemic and lymphoma cell lines, and T‐ALL blasts derived from relapse/refractory patients. In addition, CB‐103 exhibited anti‐tumor efficacy in multiple in vivo models of NOTCH‐driven T‐ALL using T‐ALL cell lines and patients derived xenograft models. Summary/Conclusions: Toxicology studies have been completed and clinical development of CB‐103 with a first‐in‐human Phase I/IIA clinical study in advanced solid tumors and haematological malignancies is under preparation.