Pharmacological disruption of the Notch transcription factor complex

Abstract

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

“…Although clinical trials with GSIs in patients with glioma have been reported, positive effects have only been seen in one study [ 151 , 152 ]. Given the broad spectrum of gamma-secretase target proteins and the dose-limiting toxicities of GSIs, it would be interesting to test the effects of small molecules that directly target the NOTCH transcriptional activation complex in glioma [ 153 , 154 , 155 ]. Considering the extensive intertumoral heterogeneity in glioma, it is possible that NOTCH inhibition would be beneficial only in a proportion of molecularly selected patients in a personalized therapy.…”

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

“…Another novel type inhibitor is FLI-06 [ 109 ] which disrupts Notch trafficking and processing. A particularly promising novel type Notch inhibitor is CB-103, which directly targets the NOTCH transcriptional activation complex [ 110 ]. New pharmacological developments concerning the specific inhibition of Notch are summarized in [ 111 ].…”

Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders

“…By blocking specific Notch ligand and receptor paralogs, these antibodies have the potential to bypass some of the systemic effects of pan-Notch inhibition, thus increasing the therapeutic window. Finally, recent work reported the discovery of CB-103, a new orally active small molecule inhibitor of the Notch transcription activation complex, providing an alternative path to therapeutic Notch inhibition (Lehal et al, 2020). To facilitate understanding of currently available therapeutic interventions, we provide a list of key existing reagents together with their most advanced stage of development to date (Table 1).…”

“…Indeed, pharmacological PSEN1 inhibition by MRK-560 attenuated T-ALL growth in mice (Habets et al, 2019). As a separate approach, Lehal et al (2020) recently reported the development of CB-103, a firstin-class inhibitor of the Notch transcription complex. CB-103 showed promising preclinical activity in the treatment of T-ALL and other Notch-dependent tumors, including GSI-resistant cell lines, without inducing significant intestinal toxicity for reasons that remain to be fully clarified.…”