New Class Of Drug Kills Lymphoma Cells

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BlankNew Class Of Drug Kills Lymphoma Cells

15 Apr 2010

Researchers from the Sackler Center at Weill Cornell Medical College have

designed a new class of drugs that targets BCL6, a master regulatory protein

responsible for causing the most common type of non-Hodgkin's lymphoma.

Findings published in today's issue of Cancer Cell show that an experimental

compound designed by a team of researchers from Weill Cornell Medical College,

the University of land and the Ontario Cancer Center at the University of

Toronto may effectively block the cancer-causing actions of BCL6 by attaching to

a critical " hot spot " on its surface, thus killing off the cancer cells.

" BCL6 mediates its cancer-causing actions by attaching to other proteins, "

explains Dr. Ari Melnick, associate professor of medicine from the and

Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell

Medical College. " Traditionally protein-protein interactions have been viewed as

being too difficult to block with small-molecule drugs. "

Accordingly, by observing the atomic scale structure of BCL6 attached to its

partner proteins, Dr. Melnick and colleagues identified a critical " hot spot "

that appeared to be amenable to designing a drug. Dr. Mackerell, from

the University of land, then used computational modeling to identify

chemical structures that could attack this hot spot.

" We tested the ability of a large number of these chemicals to bind and block

BCL6, " said Dr. Melnick, " and then Dr. Gilbert Privé, from the University of

Toronto, performed nuclear magnetic resonance and X-ray crystallography studies

to show that a specific BCL6 inhibitor compound hit exactly in the center of the

predicted hot spot. Our results show that given the right scientific approach it

is quite possible to design drugs against key protein regulatory factors like

BCL6. "

Dr. Melnick's group showed that the BCL6 inhibitor was specific for BCL6 and did

not block other master regulators, and that the experimental drug could

powerfully kill DLBCL cells derived from human patients with this disease.

Remarkably, the compound was completely non-toxic to animals, and could

powerfully suppress and improve survival in animal models.

" This means that if given as a therapeutic agent, the compound would be unlikely

to have ill-effects on healthy normal cells, and therefore would not be expected

to have significant side effects, " explains Dr. Melnick. " Since emerging data

implicates BCL6 in other tumor types in addition to non-Hodgkin's lymphoma, it

is possible that BCL6-targeted therapy could benefit many other cancer

patients. "

Dr. Melnick is among the physician-scientists supported by the Leukemia and

Lymphoma Society's (LLS) Scholar Award Program. Since 2005, LLS has funded

research in Dr. Melnick's laboratory, much of which has been focused on

developing better treatments for patients with B-cell lymphomas. Dr. Melnick is

also the leader of a Waxman Cancer Research Foundation Program Grant,

which directly supported the effort to design small molecules for the BCL6 hot

spot by the Melnick, Privé and Mackerell research team. The results of Dr.

Melnick's work in this area led the LLS to form a drug discovery partnership

with Forma Therapeutics to improve these drugs so they can be used in human

clinical trials for hematological malignant cancers.

Source

Weill Cornell Medical College

Article URL: http://www.medicalnewstoday.com/articles/185462.php

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