Interesting article...

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HHMI: Medical Institute: Studies Reveal How New Drug May

Overcome Deadly Mutation that Causes Leukemia

By CJ - Webbolt Newsroom

January 23, 2006, 15:08

HHMI researchers have discovered how a new generation of drugs thwarts

a deadly mutation that causes chronic myelogenous leukemia (CML).

Although the drug Gleevec, which is manufactured by Novartis, is

considered the standard of treatment for CML, certain patients develop

resistance to the drug. Resistance is usually caused by mutations that

alter the shape of an enzyme called Abl that is targeted by Gleevec.

Once the shape of the enzyme is changed, the drug does not bind as

effectively to its target.

" We found that dasatinib overcomes all of these Gleevec-resistant

mutants, with the exception of T315I. So, the remaining unturned stone

has been to find a drug to treat T315I. " - L. Sawyers

Using x-ray crystallography, the scientists produced detailed

molecular images that reveal how VX-680, a drug developed by Vertex

Pharmaceuticals and Merck, interacts with a mutant form of Abl. The

new studies, published in the January 15, 2006, issue of the journal

Cancer Research, hint at how VX-680 jams the mutant Abl enzyme and

stops proliferation of cancerous cells. HHMI researchers Kuriyan

at the University of California, Berkeley, and Sawyers at the

Jonsson Comprehensive Cancer Center at UCLA, led the research teams

that collaborated on the studies.

One of the more problematic mutations in Abl is called T315I, and it

is responsible for about 15 percent of cases in which CML patients

develop resistance to Gleevec. The T315I mutation also confers

resistance to dasatinib, a newer drug developed by Bristol-Myers

Squibb that has been effective in phase I and phase II trials as a

second line of defense in patients who develop resistance to Gleevec.

The T315I mutation is particularly troublesome because it sits at the

heart of the enzyme's catalytic center, said Kuriyan, and blocks the

binding of Gleevec and dasatinib.

" More than fifty mutations have been described that cause resistance

to Gleevec, " said Sawyers. " We found that dasatinib overcomes all of

these Gleevec-resistant mutants, with the exception of T315I. So, the

remaining unturned stone has been to find a drug to treat T315I.

" By good luck, in collaboration with Ambit Biosciences, we found that

VX-680, now in clinical trials as an inhibitor of another kinase

called Aurora, also inhibits the T315I mutant. However, it is

important to understand how VX-680 binds to this mutant to inhibit it,

whereas the other drugs do not, " said Sawyers. That new knowledge

could aid in developing a strategy for searching for other drugs that

could inhibit resistant mutants.

Abl is an enzymatic switch called a kinase that becomes overactivated

by a chromosomal mix-up that occurs during blood cell development. The

genes ABL and BCR, which are located on different chromosomes, become

fused and express a hybrid Bcr-Abl enzyme that is always active. The

hyperactive Bcr-Abl, in turn, drives the overproliferation of white

blood cells that is the hallmark of CML. In earlier studies, Sawyers

and his colleagues showed that dasatinib could overcome a significant

proportion of the resistant mutants.

In the experiments reported in the Cancer Research article, Kuriyan

and his colleagues used x-ray crystallography to produce molecular

images that give researchers a better idea of how VX-680 binds to the

T315I mutant version of Bcr-Abl. In x-ray crystallography, x-rays are

directed through crystals of a protein or a drug-and-protein complex,

and the resulting diffraction pattern is analyzed by researchers and

used to deduce the structure of the complex under study.

While the researchers were not able to create useful crystals of the

complex of VX-680 with a T315I mutant Bcr-Abl, the current studies

show the structure of VX-680 in complex with another Abl mutant,

H396P, which is resistant to Gleevec.

The Abl kinase, like other kinases, can assume active or inactive

conformations, and the researchers' structural analysis revealed that

the H396P mutation caused the enzyme to favor an active conformation.

The researchers found that VX-680 was effective at blocking this

mutant because it could recognize and bind to an active conformation,

said Kuriyan. In contrast, Gleevec and dasatinib act by recognizing an

inactive conformation and binding to it, rendering the Abl kinase

inactive.

" Thus, this structure does help explain why VX-680 has activity

against the T315I mutation, and that arises from the shape of VX-680, "

said Kuriyan. " While Gleevec penetrates deeply into the kinase domain

of Abl, VX-680 stays away from the position of the T315I mutation,

leaving a significant gap. " This gap allows VX-680 to accommodate the

mutation and still bind to the mutant Abl.

In additional experiments, Sawyers and his colleagues tested VX-680's

effectiveness against CML cells isolated from a patient with the T315I

mutation. The studies showed that the drug inhibited T315I mutant

BCR-ABL in the cancer cells.

" This offers a very useful predictive tool that tells us that the drug

does work against the mutation, " said Sawyers. " It gives us confidence

that we can now take the drug into clinical trials. " Tests are already

underway to determine the effectiveness of the drug in leukemia

patients, including those with the T315I mutation.

© Copyright 2006 - Webbolt Company Limited All rights reserved.

[Guest guest]

reat Article ,

I have been reading about this since ASH and it is really neat to

see how this is coming along nicely.

Cheers,

Cheryl-Anne

>

> HHMI: Medical Institute: Studies Reveal How New Drug

May

> Overcome Deadly Mutation that Causes Leukemia

> By CJ - Webbolt Newsroom

> January 23, 2006, 15:08

>

> HHMI researchers have discovered how a new generation of drugs

thwarts

> a deadly mutation that causes chronic myelogenous leukemia (CML).

>

> Although the drug Gleevec, which is manufactured by Novartis, is

> considered the standard of treatment for CML, certain patients

develop

> resistance to the drug. Resistance is usually caused by mutations

that

> alter the shape of an enzyme called Abl that is targeted by

Gleevec.

> Once the shape of the enzyme is changed, the drug does not bind as

> effectively to its target.

>

> " We found that dasatinib overcomes all of these Gleevec-resistant

> mutants, with the exception of T315I. So, the remaining unturned

stone

> has been to find a drug to treat T315I. " - L. Sawyers

>