Thursday, June 19, 2014
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leukemia (CLL); mantle cell lymphoma (MCL); multiple myeloma (MM)
Endoplasmic reticulum to nucleus signaling 1 (ERN1;
Cell culture and mouse
studies suggest inhibiting IRE1 and Btk could help treat CLL, MCL and MM.
Chemical synthesis and in vitro testing of chromenone analogs
identified compounds that inhibited the activity of IRE1's RNase domain with
nanomolar to low micromolar potency. In a transgenic mouse model of CLL, one
lead inhibitor decreased CLL cell levels in peripheral blood compared with vehicle.
In CLL cells from the mouse models and human CLL, MCL and MM cell lines, the
IRE1 inhibitor plus the Btk inhibitor Imbruvica
caused more potent growth inhibition than either agent alone. Ongoing work
includes testing IRE1 inhibitors and ibrutinib in mouse models of B cell
Inc. and Johnson
& Johnson market Imbruvica to treat CLL and MCL. The
compound is in Phase III testing to treat B cell lymphoma and non-Hodgkin's
lymphoma (NHL) and Phase II testing to treat MM and lymphoma.
Corp. has the covalent small molecule Btk inhibitor AVL-292
in Phase I testing to treat CLL and B cell lymphoma.
Pharmaceutical Co. Ltd. has the Btk inhibitor ONO-4059
in Phase I testing to treat B cell lymphoma.
Published online June 19, 2014
For findings from both
studies, patent application filed by the H.
Lee Moffitt Cancer Center & Research Institute;
available for licensing
Ranatunga, S. et al. J.
published online April 21, 2014;
Tang, C.-H.A. et al. J. Clin. Invest.;
published online May 8, 2014;
Contact: Chih-Chi Andrew Hu, H. Lee
Moffitt Cancer Center & Research Institute, Tampa, Fla.
Contact: Juan R. Del Valle, same affiliation as above
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