| Literature DB >> 23434461 |
Giovanni Roti1, Anne Carlton, Kenneth N Ross, Michele Markstein, Kostandin Pajcini, Angela H Su, Norbert Perrimon, Warren S Pear, Andrew L Kung, Stephen C Blacklow, Jon C Aster, Kimberly Stegmaier.
Abstract
Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small-molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia-associated mutation. Sarco/endoplasmic reticulum calcium ATPase (SERCA) channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G0/G1 arrest in NOTCH1-mutated human leukemia cells. A small-molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling in Drosophila. These studies "credential" SERCA as a therapeutic target in cancers associated with NOTCH1 mutations.Entities:
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Year: 2013 PMID： 23434461 PMCID： PMC3709972 DOI： 10.1016/j.ccr.2013.01.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743