Gemin X's Pan-Bcl-2 Antagonist GX15-070 Permits Rational Combination with Velcade in Mantle Cell Lymphoma
- Data Presented in an Oral Presentation at American Society of
Hematology Annual Meeting -
Montréal, Canada – December 13, 2006 – Gemin X Biotechnologies, Inc. announced today that results from a preclinical study of GX15-070 in mantle cell lymphoma (MCL) cell lines and ex vivo patient samples showed that GX15-070 and bortezomib (Velcade) exhibit synergistic activity, due to the ability of GX15-070 to potently antagonize the Bcl-2 family member, Mcl-1. Gemin X co-founder and chief scientific officer Gordon Shore, Ph.D., presented these data (Abstract 832) at the American Society of Hematology’s 48th Annual Meeting and Exposition, December 9-12 in Orlando, FL during an oral presentation titled “Obatoclax (GX15-070) Is a Potent Antagonist of Constitutive Mcl-1/Bak Interactions in Intact Mitochondrial Membrane and Synergizes with Bortezomib in Mantle Cell Lymphoma.”
The preclinical study evaluated the potency of GX15-070 in situ on the native Bcl-2 protein-protein interaction between the Mcl-1 and Bak proteins. Employing chemical crosslinking to detect Mcl-1/Bak dimers in intact mitochondrial membranes, GX15-070 was found to potently disrupt these interactions. GX15-070 was previously shown to target interactions involving all pro-survival Bcl-2 protein family members including Bcl-2, Bcl-Xl, Mcl-1, Bcl-w, A1 and Bcl-b. The pan-inhibitor properties of GX15-070 were confirmed by its demonstrated ability to reinstate Bax or Bak toxicity otherwise held in check by Bcl-2, Bcl-Xl, Mcl-1, or Bcl-w. Additionally, as Mcl-1 is subject to rapid degradation by proteasomes, the proteasome inhibitor bortezomib was found to enhance Mcl-1 protein levels. As predicted, a combination of GX15-070 and bortezomib proved more effective than either drug alone in mantle cell lymphoma.
“These results demonstrate an important aspect of GX15-070: the compound’s ability to disrupt interactions in all pro-survival protein members, which makes it less likely that any one member or another will overcome the compound’s effectiveness,” said Shore. “These findings also provide a strong biochemical rationale to evaluate a combination of GX15-070 and bortezomib in clinical trials directed at mantle cell lymphoma.”
About GX15-070
GX15-070 is designed to restore apoptosis, the natural process of cell death that is often inhibited in cancer cells. Over-expression of the Bcl-2 protein family inhibits apoptosis and has been observed in a wide range of cancers, including those of the lymph, breast, lung, prostate and colon. GX15-070 is specifically designed to inhibit all of the anti-apoptotic members of the Bcl-2 protein family, thus inducing apoptosis in cancer cells without damaging normal cells, and is the first such small molecule, pan-inhibitor of Bcl-2 proteins tested in clinical trials.
Gemin X Biotechnologies Inc. specializes in the discovery and development of novel small-molecule cancer therapeutics based on the regulation of apoptosis, the body’s natural ability to destroy injured or damaged cells. Gemin X’s lead product, GX15-070, is a small molecule, pan-inhibitor of Bcl-2 proteins in Phase 2 clinical trials. Gemin X is also developing a small molecule that induces apoptosis in p53-defective cancers, which is slated for an IND filing at the end of the year. Gemin X is privately held and is located in Montréal, Quebec and Malvern, Pennsylvania.
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