It functions to decrease the amount of her 2 receptor(both by being a tyrosine kinase inhibitor like lapatinib and by ubiquinating** her2 and ERa), and the amount of ER alpha receptor and although it increased heat shock protein 70 it also encouraged HSP70 to complex with her2 and ERa and get ubiquinated together, it also seemed to act as a HSP 90 inhibitor (good as Hsp 90 helps her2 and ERa "client proteins"
Lapatinib given neoadjuvantly tends to result in increased ERa so having a TKi type drug which works on ERa and her2 simultaneously is an advantage.
I guess my question is, does it have an effect on EGFR or particularly her3?
How about IGFR1. These are pathways her2+ bcs use to escape herceptin and lapatinib.
Sounds very promsing
**ubiquination is a way of marking cell products for the trash collectors to take them away to destroy them
J Cell Biochem. 2011 Apr 18. doi: 10.1002/jcb.23147. [Epub ahead of print]
Ubiquitination and downregulation of ErbB2 and estrogen receptor-alpha by kinase inhibitor MP-412 in human breast cancer cells.
Suzuki T, Fujii A, Ochi H, Nakamura H.
Source
Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
suzuki.tsuyoshi@mf.mt-pharma.co.jp.
Abstract
ErbB2 has been proven to be an important target for breast cancer therapy. MP-412 is a dual ErbB2 and epidermal growth factor receptor tyrosine kinase inhibitor belonging to an irreversible-type anilinoquinazoline derivative. We demonstrate herein that along with the kinase inhibition, MP-412 has the ability to induce ubiquitination, internalization, and degradation of ErbB2 in several human breast cancer cell lines at concentrations relatively higher than those required for kinase inhibition. Another irreversible inhibitor, CI-1033, showed similar activity, while the reversible compounds were ineffective, suggesting a crucial role of covalent bonding functionality in these effects. In MCF7 cells, MP-412 depleted not only ErbB2 but also estrogen receptor (ER)-α, and to some extent, affected Raf-1, while MP-412 activated Hsp70 expression. Moreover, we observed that MP-412 increased immunocomplexing of Hsp70 with ErbB2 and ER-α, with simultaneous induction of ubiquitination of these client proteins. Furthermore, in combination with proteasome inhibitor, MP-412 resulted in the noticeable accumulation of ErbB2 and ER-α in the detergent insoluble fraction of cell lysates. These results suggest that MP-412 acts as an inhibitor of Hsp90 function, whereas MP-412 did not bind directly to ATP-binding site of Hsp90, unlike geldanamycin. We also found that new protein synthesis was involved in the activity of MP-412 on Hsp90 modulation. Since downregulation of ErbB2 and ER-α by accelerating the ubiquitin-proteolysis system will become an attractive approach for breast cancer therapy, we expect MP-412 to be a lead compound for the drug design and the development of such agents. J. Cell. Biochem. © 2011 Wiley-Liss, Inc.
Copyright © 2011 Wiley-Liss, Inc.
PMID: 21503962
new drug being developed with an exciting combination of attributes !!
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