Data Presented at the 2015 AACR Annual Meeting Provide Strong Rationale for the Combination of Alvocidib with Inhibitors of BET Proteins.
SALT LAKE CITY, UT, USA I April 24, 2015 I Tolero Pharmaceuticals, Inc, today announced that it presented nonclinical study results demonstrating profound synergy of lead candidate, alvocidib, and bromo and extra terminal (BET) protein inhibitors in acute myeloid leukemia (AML) models at the 2015 American Association for Cancer Research Annual Meeting in Philadelphia, PA. Alvocidib is a CDK9 inhibitor in clinical development for the treatment of frontline and relapsed/refractory AML. In the data presented, the combination of CDK9 and BET protein inhibitors led to a synergistic inhibition of the super enhancer complex (SEC). The SEC is a group of transcriptional regulators that can cause tumorigenesis and disease progression in AML, and inhibitors of this complex are the focus of many drug development efforts.
“Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia.”
Steven L. Warner, Ph.D. VP, Discovery and Development of Tolero, commented that, “The inhibition of CDK9 by alvocidib and BRD4 inhibition by several small molecules, demonstrates strong synergy in targeting super enhancer transcriptional programs that drive oncogenesis in AML and other malignancies. We will consider this combination as we seek to expand our clinical strategy of alvocidib in AML to provide the greatest value to patients in need.”
The results were reported in the abstract and presentation entitled, “Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia.” The study utilized several cell-based and animal models of AML to demonstrate that alvocidib had potent synergistic activity when combined with several different BET protein inhibitors that are in various stages of clinical or preclinical development. In these models, sub-efficacious doses of alvocidib and BET inhibitors as single agents were combined to attain complete tumor regressions in xenograft studies, down regulate SEC transcriptional activity, and potently induce apoptosis in AML cells. These findings provide strong rationale for combining alvocidib with a BET inhibitor in future clinical studies.
Alvocidib demonstrated consistent and compelling clinical activity in Phase 2 studies as part of a novel combination regimen in patients with AML, and Tolero intends to initiate a Phase 3 registration study of alvocidib in combination with chemotherapy compared to chemotherapy alone in patients with relapsed or refractory AML in the second half of 2015.
About Alvocidib
Alvocidib is a potent small molecule inhibitor of cyclin-dependent kinases (CDKs) in development as a combination therapy for frontline and relapsed/refractory AML. CDKs are regulatory proteins that are critical to cellular replication and regulation of gene expression. Given the key role CDK de-regulation plays in unchecked cell division, proliferation and expression of cancer-associated genes, CDKs are an attractive target for the treatment of various cancers.
About Tolero
Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with serious oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias and anemia as well as important targets of drug resistance and transcriptional control. www.toleropharma.com
SOURCE: Tolero Pharmaceuticals
Post Views: 75
Data Presented at the 2015 AACR Annual Meeting Provide Strong Rationale for the Combination of Alvocidib with Inhibitors of BET Proteins.
SALT LAKE CITY, UT, USA I April 24, 2015 I Tolero Pharmaceuticals, Inc, today announced that it presented nonclinical study results demonstrating profound synergy of lead candidate, alvocidib, and bromo and extra terminal (BET) protein inhibitors in acute myeloid leukemia (AML) models at the 2015 American Association for Cancer Research Annual Meeting in Philadelphia, PA. Alvocidib is a CDK9 inhibitor in clinical development for the treatment of frontline and relapsed/refractory AML. In the data presented, the combination of CDK9 and BET protein inhibitors led to a synergistic inhibition of the super enhancer complex (SEC). The SEC is a group of transcriptional regulators that can cause tumorigenesis and disease progression in AML, and inhibitors of this complex are the focus of many drug development efforts.
“Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia.”
Steven L. Warner, Ph.D. VP, Discovery and Development of Tolero, commented that, “The inhibition of CDK9 by alvocidib and BRD4 inhibition by several small molecules, demonstrates strong synergy in targeting super enhancer transcriptional programs that drive oncogenesis in AML and other malignancies. We will consider this combination as we seek to expand our clinical strategy of alvocidib in AML to provide the greatest value to patients in need.”
The results were reported in the abstract and presentation entitled, “Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia.” The study utilized several cell-based and animal models of AML to demonstrate that alvocidib had potent synergistic activity when combined with several different BET protein inhibitors that are in various stages of clinical or preclinical development. In these models, sub-efficacious doses of alvocidib and BET inhibitors as single agents were combined to attain complete tumor regressions in xenograft studies, down regulate SEC transcriptional activity, and potently induce apoptosis in AML cells. These findings provide strong rationale for combining alvocidib with a BET inhibitor in future clinical studies.
Alvocidib demonstrated consistent and compelling clinical activity in Phase 2 studies as part of a novel combination regimen in patients with AML, and Tolero intends to initiate a Phase 3 registration study of alvocidib in combination with chemotherapy compared to chemotherapy alone in patients with relapsed or refractory AML in the second half of 2015.
About Alvocidib
Alvocidib is a potent small molecule inhibitor of cyclin-dependent kinases (CDKs) in development as a combination therapy for frontline and relapsed/refractory AML. CDKs are regulatory proteins that are critical to cellular replication and regulation of gene expression. Given the key role CDK de-regulation plays in unchecked cell division, proliferation and expression of cancer-associated genes, CDKs are an attractive target for the treatment of various cancers.
About Tolero
Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with serious oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias and anemia as well as important targets of drug resistance and transcriptional control. www.toleropharma.com
SOURCE: Tolero Pharmaceuticals
Post Views: 75
