Small Molecules That Inhibit Notch Signaling
The proteolytic processing of Notch receptors plays a central role in the transduction of Notch signaling, which is involved in a variety of important processes in the body. Abnormal Notch processing has been implicated in a variety of cancers. γ-Secretase is responsible for the third and last cleavage step of Notch receptors. Since γ-secretase plays an important role in Alzheimer’s disease, great effort has been spent to develop γ-secretase inhibitors (GSIs). The majority of these inhibitors block γ-secretase nonselectively, which means that these compounds can be used to block Notch cleavage and thereby regulate Notch signaling. In this review we give an overview of the most-used GSIs in the Notch field, together with examples of their use. It is a huge advantage that these drug-like compounds are already optimized for γ-secretase, and some are already being used in clinical trials. However, their nonspecificity has disadvantages as well, since four Notch receptors exist with different sites of expression and different roles in cell signaling and at least four different γ-secretase proteases are involved in their cleavage. It would be worth the effort to screen many GSIs for their selectivity for the different Notch receptors and γ-secretases, in order to obtain interesting tools for further research and—in the end—to develop safer drugs.
Key wordsNotch γ-secretase inhibitors Transition-state analogs Allosteric inhibitors Selectivity
This work was supported by VIB, a Methusalem grant from KU Leuven and the Flemish government, Janssen Pharmaceutica, and the Arthur Bax and Anna Van Luffelen foundation.
- 27.Churcher I, Williams S, Kerrad S et al (2003) Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of an asymmetric Ireland-Claisen rearrangement. J Med Chem 46:2275–2278PubMedCrossRefGoogle Scholar
- 29.Quesnelle C, Kim S-H, Lee F, et al. (2012) Bisfluoroalkyl-1,4-benzodiazepinone compounds WO/2012/129353Google Scholar
- 65.DeAngelo DJ, Stone RM, Silverman LB (2006) A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol 24(18S):6585Google Scholar