AT9283 & Genetic Instability of BCR-ABL

[Guest guest]

Full presentations will be found at cited URLs:

" HAEMATOLOGICAL MALIGNANCIES: AT9283 is also being investigated in a Phase I/II

open label, dose escalation trial to assess the safety, tolerability and

preliminary efficacy of AT9283 as monotherapy in patients with acute leukaemias.

The trial is being conducted at two centres in the USA. Our current plans are to

explore the potential of AT9283 to treat patients with acute myeloid leukaemia

and possibly other haematological malignancies including myelofibrosis, chronic

myeloid leukaemia, and high risk myelodysplastic syndromes. We are also

investigating the possibility of using an oral formulation. To learn more about

the development status of this compound, please see the most recent Astex

presentations. " Undated article.

http://www.astex-therapeutics.com/products/pipeline.php#

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ENGLAND Playing Role In Development of Aurora Kinases Inhibitors.

" Aurora kinases play a key role in the regulation of mitosis and in recent years

have become attractive targets for the treatment of cancer. X-ray

crystallographic structures were generated using a novel soakable form of Aurora

A and were used to drive the optimization toward potent dual Aurora A/Aurora B

inhibitors. These compounds inhibited growth and survival of HCT116 cells and

produced the polyploid cellular phenotype typically associated with Aurora B

kinase inhibition. Optimization of cellular activity and physicochemical

properties ultimately led to the identification of compound 16 (AT9283). In

addition to Aurora A and Aurora B, compound 16 was also found to inhibit a

number of other kinases including JAK2 and Abl (T315I). This compound

demonstrated in vivo efficacy in mouse xenograft models and is currently under

evaluation in phase I clinical trials. "

http://pubs.acs.org/action/doSearch?action=search & searchText=AT9283 & qsSearchArea\

=searchText & type=within & publication=40026035

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OVERCOMING DRUG RESISTANCE IN CML DRUGS:

" In an accompanying editorial, Margret Rodrigues, Ph.D., and Sattler,

Ph.D., of the Dana Farber Cancer Institute in Boston, discuss the possible

causes of genetic instability in the BCR-ABL gene and future approaches to

developing successful therapies for chronic myeloid leukemia. " A future

challenge will be to devise approaches that overcome drug resistance within

these [chronic myeloid leukemia stem] cells without selecting for additional

drug-resistant populations, " the authors write.

J Natl Cancer Inst 2007; 99: 680-693

http://www.sciencedaily.com/releases/2007/05/070501160703.htm

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WHY STEM CELLS SURVIVE WITH IMATINIB

" The autophagy process allows stem cells to survive treatment with imatinib, and

continue to survive. The researchers used chloroquine to see if it would have an

effect on imatinib treatment. The dual treatment with imatinib and chloroquine

eliminated most CML stem cells. Also, imatinib-induced cell death was

significantly increased in mice inoculated with p210BCR/ABL-expressing cells. "

Source:

Shafer

Jefferson University

http://www.medicalnewstoday.com/articles/145944.php

" The therapeutic effects of the blockbuster leukemia drug imatinib may be

enhanced when given along with a drug that inhibits a cell process called

autophagy, researchers from the Kimmel Cancer Center at Jefferson reported in

the Journal of Clinical Investigation. "

http://www.medstore.biz/news/65220/adding-chloroquine-imatinib-improves-therapeu\

tic-effect/

FYI,

Lottie Duthu