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Small molecule blockade of
transcriptional coactivation of the hypoxia-inducible factor pathway
Andrew L. Kung, Sonya D. Zabludoff, Dennis S. France,
Steven J. Freedman, Elizabeth A. Tanner, Annelisa Vieira, Susan Cornell-Kennon,
Jennifer Lee, Beqing Wang, Jamin Wang, Klaus Memmert, Hans-Ulrich Naegeli, Frank
Petersen, Michael J. Eck, Kenneth W. Bair, Alexander W. Wood, and David M.
Livingston
Dana-Farber Cancer Institute and
Harvard Medical School, Boston, MA 02115 USA [A.L.K., S.J.F., E.A.T., A.V.,
M.J.E., D.M.L.]; Department of Pediatric Oncology, Dana-Farber Cancer Institute,
and Children's Hospital, Boston, MA 02115 USA [A.L.K.]; Novartis Pharmaceuticals
Corporation, Oncology Department, Cambridge, MA 02139 USA [S.D.Z., D.S.F.,
S.C.-K., J.L., B.W., J.W., K.W.B., A.W.W.]; Division of Hematology/Oncology,
Beth Israel Deaconess Medical Center, Boston, MA 02115 USA [S.J.F.]; Novartis
Pharma AG Natural Products Unit/Discovery Technologies, Basel, Switzerland
CH-4002 [K.M., H.-UN., F.P.]; Present address: AstraZeneca, Cancer Discovery, R
& D Boston, Waltham, MA 02451 USA [S.D.Z.]; Present
address: Merck Research Laboratories, West Point, Pennsylvania 19486 [S.J.F.];
Present address: Chiron Corporation, Emeryville, California 94608 [K.W.B.]. Correspondence: A.L.K., (617)
632-5731 (phone), (617) 632-4381 (fax), andrew_kung@dfci.harvard.edu; D.M.L,
(617) 632-2203 (phone),
(617) 632-4381 (fax), david_livingston@dfci.harvard.edu .
Homeostasis under hypoxic conditions is maintained through a coordinated
transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway
and requires coactivation by the CBP and p300 transcriptional
coactivators.
Through a target-based high-throughput screen, we identified chetomin as a
disrupter of HIF binding to p300.
At a molecular level, chetomin disrupts the structure of the CH1 domain of p300
and precludes its interaction with HIF, thereby attenuating hypoxia-inducible
transcription.
Systemic administration of chetomin inhibited hypoxia-inducible transcription
within tumors and inhibited tumor growth.
These results demonstrate a therapeutic window for pharmacological attenuation
of HIF activity and further establish the feasibility of disrupting a signal
transduction pathway by targeting the function of a transcriptional coactivator
with a small molecule.
Copyright © 2004 Cell Press.
Source: http://www.cancercell.org/content/article/abstract?uid=PIIS153561080400176X
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