BMS-214662, a cytotoxic farnesyltransferase inhibitor (FTI), has been shown to target primitive progenitor cells (PPC) in CML

[Guest guest]

Abstract

We have discovered a number of distinct classes of inhibitors of the enzyme

farnesyltransferase, an attractive new therapeutic target in oncology. The

inhibitor classes include ones that are farnesylpyrophosphate-based,

bisubstrates, thiol- and imidazole-based tetrapeptides, imidazole-based

dipeptides and ultimately imidazole-based tetrahydrobenzodiazepines. The latter

class yielded

®-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-\

thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), which has entered clinical

trials.

http://pubs.acs.org/doi/pdfplus/10.1021/bk-2001-0796.ch012

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Molecular Pathways: Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant

Philadelphia Chromosome-Positive Leukemia

a.. O'Hare,

b.. W.N. Deininger,

c.. A. Eide,

d.. Tim Clackson,

e.. and J. Druker

Clin Cancer Res January 15, 2011 17:212-221; Published OnlineFirst November 22,

2010; doi:10.1158/1078-0432.CCR-09-3314

....in quiescent CML progenitors that were not eliminated by imatinib alone (66),

or the mechanistically unexplained ability of BMS-214662, a farnesyl transferase

inhibitor, to induce apoptosis in primitive CML cells (68). A completely

different approach is immunotherapy...

There is also emerging data on some of the new drugs under development

suggesting that these recalcitrant clones can be inhibited. BMS-214662, a

cytotoxic farnesyltransferase inhibitor (FTI), has been shown to target

primitive progenitor cells (PPC) in CML. In long-term culture-initiating cell

(LTC-IC) assays with both chronic-phase CML and normal CD34+ progenitors,

addition of BMS-214662 to dasatinib in vitro has been shown to dramatically

reduce the PPC colonies and also overcome kinase domain mutation transfectants

in Baf3 cell lines.

..aacrjournals.org/content/17/2/212.abstract

http://www.medscape.com/viewarticle/576209_6

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BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and

progenitor cells and synergizes with tyrosine kinase inhibitors

Mhairi Copland1, Francesca Pellicano1, Richmond2, Elaine K. Allan1,

Hamilton1, Francis Y. Lee3, o Weinmann3, and Tessa L. Holyoake1

To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic

farnesyltransferase inhibitor, previously reported to kill nonproliferating

tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML

stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone

or in combination with IM or dasatinib, potently induced apoptosis of both

proliferating and quiescent CML stem/progenitor cells with less than 1% recovery

of Philadelphia-positive long-term culture-initiating cells. Normal

stem/progenitor cells were relatively spared by BMS-214662, suggesting

selectivity for leukemic stem/progenitor cells. The ability to induce selective

apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not

seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic

against CML blast crisis stem/progenitor cells, particularly in combination with

a tyrosine kinase inhibitor and equally effective in cell lines harboring

wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first

report of an agent with activity in resistant and blast crisis CML that

selectively kills CML stem/progenitor cells through apoptosis and offers

potential for eradication of chronic phase CML.

We hypothesized that BMS-214662 might therefore target quiescent CML

stem/progenitor cells and synergize with TKIs, which induce potent

antiproliferative effects on CML stem/progenitor cells. We show that BMS-214662

selectively induces apoptosis of CML stem/progenitor cells, both in vitro and in

vivo, and synergizes with IM or dasatinib to kill stem/progenitor cells

reversibly arrested in G1.

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/111/5/2843

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Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With

Acute Leukemias and High-Risk Myelodysplastic Syndromes

Cortes, Stefan Faderl, Elihu Estey, Razelle Kurzrock, Deborah ,

Miloslav Beran, Guillermo -Manero, Alessandra Ferrajoli, Francis Giles,

Koller, O'Brien, , A. Bai, Hagop Kantarjian

http://jco.ascopubs.org/content/23/12/2805.full

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FYI,

Lottie Duthu