Abstract 1163: Non clinical pharmacology, pharmacokinetics and safety profiling of CB-103: A novel first-in-class small molecule inhibitor of the NOTCH pathway

NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling 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. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway by producing truncated version of NOTCH1 or NOTCH2. Over activation of NOTCH and its oncogenic role in various cancers is prognostically relevant with shorter survival seen in patients harbouring these genetic alterations. Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. 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 γ-secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of mAbs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach would be the blockage of NOTCH signalling by targeting the most downstream complex in the NOTCH signal transduction cascade, the NOTCH transcriptional activation complex, using small molecule inhibitors. Previously we have reported the discovery and characterization of CB-103, a novel first-in-class orally-active small molecule inhibitor of the NOTCH pathway. CB-103 inhibits NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus. CB-103 has shown the ability to block NOTCH signalling in various human cancer cell lines with active NOTCH pathway. CB-103 has also been tested in in vivo models. In a GSI/mAb resistant model of human triple negative breast cancer, CB-103 has demonstrated excellent anti-tumor efficacy. In this study we present additional pharmacology, pharmacokinetics data and provide an overview of the good safety and tolerability seen with CB-103 in the non-clinical studies. Based on these findings CB-103 has been selected as clinical candidate to be investigated in a FIM, phase I/IIA clinical study in advanced cancer patients. Citation Format: Rajwinder Lehal, Viktoras Frismantas, Charlotte Urech, Maximilien Murone, Dirk Weber, Michael Bauer, Jean-Pierre Bourquin, Freddy Radtke. Non clinical pharmacology, pharmacokinetics and safety profiling of CB-103: A novel first-in-class small molecule inhibitor of the NOTCH pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1163. doi:10.1158/1538-7445.AM2017-1163