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Sep 11, 2014
 |  BC Innovations  |  Targets & Mechanisms

A chromatin target for ALL

A New York University School of Medicine-GlaxoSmithKline plc collaboration has shown that an inhibitor of the chromatin regulator JMJD3 could help treat T cell acute lymphoblastic leukemia.1 As JMJD3 is upregulated and used as a notch partner in T cell leukemia specifically, and not during T cell development, the researchers hope that targeting the epigenetic modulator could avoid the safety pitfalls of general notch pathway suppression.

Current treatments for T cell acute lymphoblastic leukemia (T-ALL) involve combination chemotherapy regimens that have considerable toxic side effects. Apart from drugs that inhibit BCR-ABL tyrosine kinase fusion proteins, no targeted therapies are marketed for the disease.

The notch pathway is particularly attractive for drug development because it is overactivated in the majority of T-ALLs. However, most attempts have fallen short because notch signaling is involved in many other cellular processes, and it has been difficult to find selective inhibitors that do not have severe safety liabilities.

"Current notch-targeted therapies are pan-notch inhibitors and are burdened with side effects that limit their applicability," said Patrick Trojer, head of biology at epigenetics company Constellation Pharmaceuticals Inc.

At least one notch 1 (NOTCH1)-targeted molecule, OncoMed Pharmaceuticals Inc.'s anti-NOTCH1 antibody, OMP-52M51, is in Phase I trials for solid tumors and lymphoid malignancies. The program is part of an OncoMed-GSK collaboration.

In 2012, a group led by Panagiotis Ntziachristos, a postdoctoral fellow in the laboratory of NYU School of Medicine professor Iannis Aifantis, identified...

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