Constellation Pharmaceuticals Announces Publication Demonstrating Pharmacological Suppression of Key Cancer-causing Gene

Targeting Chromatin Adaptors to Suppress MYC, a Gene Dysregulated in Wide Range of Malignancies, Represents Promising Therapeutic Approach in Oncology


CAMBRIDGE, Mass. – September 26, 2011 – Constellation Pharmaceuticals, Inc., a leading biopharmaceutical company in the field of epigenetics, today announced the publication of a paper in the Proceedings of the National Academy of Sciences (PNAS) demonstrating that MYC transcription can be suppressed using small molecule inhibitors of the BET family of chromatin adaptors. MYC is a master regulator of diverse cellular functions and has long been considered a compelling therapeutic target because of its role in many human malignancies. The paper appears in the online early edition of PNAS the week of September 26, 2011.


The MYC gene is translocated in all patients with Burkitt’s lymphoma and in a significant number of patients with multiple myeloma or a form of lymphoma known as diffuse large B-cell lymphoma. It is also frequently amplified in solid tumors. Tumor dependence on MYC sometimes occurs as a result of mutations in upstream pathways that cause it to be aberrantly expressed. Suppression of MYC transcription through the inhibition of BET protein binding to chromatin represents a promising new therapeutic approach in oncology.


“While pharmacologic inhibition of MYC function has been widely sought, to date it has been challenging due to the diverse mechanisms that drive aberrant MYC expression and the overall difficulty of disrupting protein-protein interactions,” said Jim Audia, Ph.D., chief scientific officer of Constellation Pharmaceuticals. “This history makes the publication of our new findings particularly exciting. The tool compounds that we and others have used have been valuable in revealing the therapeutic opportunity for BET inhibition, but these compounds are not ideal for in vivo or clinical application. Constellation is now advancing rapidly toward the clinic with multiple product candidates optimized to realize the full potential of this new molecular mechanism.”


In this study, Constellation scientists showed rapid, potent and dose-dependent suppression of MYC gene expression using inhibitors of BET bromodomains, a family of proteins involved in regulating gene transcription. By inhibiting the binding of BET bromodomains to chromatin, researchers were able to suppress the transcription of selected genes involved in growth control, thereby blocking proliferation and inducing the death of cancer cells.


Researchers showed that reducing MYC transcript and protein levels resulted in extensive cell death in a variety of in vitro human leukemia and lymphoma cell lines. Exposing myeloma cell lines to a BET inhibitor resulted in significant inhibition of growth in 14 of the 15 cell lines. Constellation also demonstrated that treatment with a BET inhibitor resulted in significant anti-tumor activity in a xenograft mouse model of Burkitt’s lymphoma. Animals treated with a BET inhibitor showed significantly less bone marrow infiltration by lymphoma cells, without weight loss or other obvious adverse systemic effects. Researchers also found that a BET inhibitor exhibited significant anti-tumor activity in a xenograft mouse model of acute myeloid leukemia. Mice treated with the BET inhibitor exhibited robust tumor growth inhibition (exceeding that seen with cytarabine, the standard of care) and even modest tumor regression.


Mark A. Goldsmith, M.D., Ph.D., president and chief executive officer of Constellation Pharmaceuticals, commented, “The development of small molecule BET bromodomain inhibitors represents a significant step forward in epigenetic-based drug discovery, and one that we are progressing toward the clinic. These findings suggest that our inhibitors will behave as selective therapies given their ability to target specific regulatory pathways, and that they may have broad utility as anti-cancer agents. The imperative for us now is to advance to the clinic with our structurally diverse set of BET inhibitors having the pharmacologic and pharmaceutical properties that will make them best-in-class treatments for patients. This program validates the power of our broad product engine, which leverages our deep expertise in chromatin biology and is applicable broadly across target classes.”


About Constellation Pharmaceuticals
Constellation Pharmaceuticals leverages insights from the rapidly expanding field of epigenetics
to discover and develop small molecule therapeutics for the treatment of cancer,
inflammatory/immunologic disorders and other diseases. Research at Constellation and by others
has shown that abnormal epigenetic regulation of gene expression contributes to many different
diseases. The company’s innovative product discovery engine targets both the enzymes that
modify the dynamic structure of chromatin and other proteins that interact with chromatin to
control gene expression. Restoration of normal gene expression through chromatin modulation
by highly selective and specific inhibitors promises to be a powerful avenue for the development
of important new medicines against a broad range of diseases. For more information, please visit
the company's website at