The NOTCH signaling pathway is involved in cell proliferation, differentiation and cell cycle progression. Four membrane-bound NOTCH receptors are found in mammals (NOTCH1, NOTCH2, NOTCH3 and NOTCH4), which interact with 5 different extracellular ligands (Jagged 1, jagged 2, delta like ligand 1, 3 and 4). Ligands bind NOTCH on the extracellular domain, starting the NOTCH signaling cascade, eventually resulting in release of the NOTCH intracellular domain (NICD). The NICD then translocates to the nucleus, effecting the activation of various genes, such as hairy/enhancer of split (HES).
γ-secretase is responsible for cleavage of the NOTCH intracellular domain from the transmembrane portion of the protein. Inhibitors of γ-secretase (GSIs) therefore are useful as inhibitors of the NOTCH signaling cascade. NOTCH signaling inhibitors have been extensively studied in hematological malignancies, as well as other cancerous tissues. LKT Laboratories offers a variety of γ-secretase inhibitors.
MK-0752 (3-[4-(4-chlorophenyl) sulfonyl-4-(2,5-difluorophenyl) cyclohexyl] propanoic acid) was also submitted for phase I clinical trials. Results of this test show that MK-0752 was tolerated by patients with advanced solid tumors, and showed efficacy as an anti-cancer agent.
DAPT (N-[N-(3,5- Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) was found to inhibit the proliferation of ovarian cancer cells, as well as inducing apoptosis of these cells. DAPT also inhibits proliferation of gastric carcinmoma cells.
These γ-secretase inhibitors and more are available from LKT Labs Inc.
Yuan X., Wu H., et al. “Notch signaling: An emerging therapeutic target for cancer treatment” Cancer Letters 369, (2015) pp 20-27. Doi: 10.1016/j.canlet.2015.07.048
Yao, Y., Ni, Y. et al. “The role of Notch signaling in gastric carcinoma: molecular pathogenisis and novel therapeutic targets.” Oncotarget. (2017) May 11. Doi: 10.18632/oncotarget.17809.
Feng, Z., Xu, W. et al. “Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer.” Oncotarget. (2017) Jan 31; 8(5):8283-8293. Doi:10.18632/oncotarget.14152.
Gu, Y., Masiero, M. and Banham AH. “Notch signaling: its roles and therapeutic potential in hematological malignancies.” Oncotarget. (2016) May 17;7(20):29804-23. Doi: 10.18632/oncotarget.7772.