– Novel oral Cdc7 inhibitor, SRA141, demonstrates competitive target selectivity and robust efficacy in several cancer models –
VANCOUVER, Canada I November 13, 2018 I Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with significant unmet needs in hematology and oncology, today reported preclinical data for its novel oral Cdc7 inhibitor, SRA141, in a poster presented at the 30th EORTC-NCI-AACR Symposium currently being held in Dublin, Ireland.
“SRA141 potently and selectively inhibits the cell division cycle kinase, Cdc7, thereby interfering with DNA replication and cell cycle dynamics within tumor cells while sparing normal cells. This unique mechanism results in significant in vitro anti-proliferative activity in a broad spectrum of tumor cell lines derived from both solid and hematologic cancers and translates into robust efficacy in rodent xenograft cancer models,” said Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. “Consistent with the observed anti-cancer activity, a pharmacodynamic assessment reveals potent on-target inhibition in both tumors and surrogate skin tissues, potentially allowing for less invasive monitoring of Cdc7 inhibition in patients.”
“We believe SRA141’s potent and selective in vitro activity, favorable in vivo pharmacokinetic properties and robust anti-tumor efficacy, particularly in colorectal cancer models, competitively positions SRA141 against other Cdc7 inhibitors and supports clinical advancement of the compound,” added Dr. Nick Glover, President and Chief Executive Officer of Sierra Oncology. “Having successfully completed the Investigational New Drug Application (IND) process with the FDA, we have prepared for a first-in-human Phase 1/2 clinical trial of SRA141 to be conducted in metastatic colorectal cancer, an indication of high unmet medical need for which SRA141 has shown considerable promise in preclinical testing.”
As reported in the poster, SRA141:
- Potently and selectively inhibits Cdc7 in in vitro biochemical assays and potently inhibits the phosphorylation of the Cdc7 substrate MCM2 in cells.
- Displays excellent selectivity with less off-target activity than competitive clinical stage Cdc7 inhibitors.
- Displays potent in vitro anti-proliferative activity against several tumor cell lines, including multiple highly sensitive colorectal tumor cell lines, with activity comparable or superior to other Cdc7 inhibitors in the majority of lines tested.
- Demonstrates excellent anti-tumor activity, including complete and partial regressions, in several in vivo tumor models representing solid (colorectal) and hematologic (B myelomonocytic leukemia, AML) cancers.
- Displays good oral bioavailability and favorable pharmacokinetics in vivo, and potent on-target inhibition (MCM2 phosphorylation) in both tumor and skin tissues.
The poster will be presented at on Tuesday, November 13th at 12:00-6:30 pm (GMT).
Title: The novel oral Cdc7 inhibitor, SRA141, demonstrates robust efficacy in preclinical cancer models
Authors: R. Hansen, S. Milutinovic, B. Strouse, M. Hedrick, G. Smith, C. Hassig
About SRA141
SRA141 is a potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). Cdc7, a serine-threonine kinase, is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.
Cdc7, together with its partner proteins Dbf4 or Drf1, is responsible for activating DNA replication during S-phase through phosphorylation and activation of the MCM2-7 helicase. Cdc7 also has functions within the DNA Damage Response (DDR) and mitosis. Over-expression of Cdc7 and its partner proteins is correlated with unfavorable clinical outcomes and poor survival in a broad range of solid tumors and hematological malignancies.
SRA141’s inhibition of Cdc7 has been shown to cause cancer cell death in a p53-independent manner and to induce tumor regression or stasis in a variety of in vivo cancer models, including complete and partial regressions in animal models of colorectal cancer.
Sierra recently reported that the U.S. Food and Drug Administration (FDA) has accepted its Investigational New Drug (IND) application for SRA141. The company plans to conduct a Phase 1/2 clinical trial designed to assess the safety and tolerability of SRA141 in patients with colorectal cancer.
Sierra Oncology retains the global commercialization rights to SRA141.
About Sierra Oncology
Sierra Oncology is a clinical stage drug development company advancing targeted therapeutics for the treatment of patients with unmet medical needs in hematology and oncology. Our lead drug candidate, momelotinib, is a potent, selective and orally-bioavailable JAK1, JAK2 and ACVR1 inhibitor that has been investigated in two completed Phase 3 trials for the treatment of myelofibrosis and has demonstrated a potentially differentiated therapeutic profile encompassing anemia-related benefits, as well as achieving substantive spleen and constitutional symptom control.
Sierra is also advancing SRA737 and SRA141. SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of cell cycle progression and the DNA Damage Response (DDR). SRA737 is currently being investigated in two Phase 1/2 clinical trials primarily focused on patients with ovarian cancer: SRA737-01, a monotherapy study, and SRA737-02, a drug combination study evaluating SRA737 potentiated by low dose gemcitabine. Sierra has also prepared for a potential clinical study of SRA737 in combination with a PARP inhibitor. SRA141 is a Phase 1 ready, potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.
SOURCE: Sierra Oncology
Post Views: 18
– Novel oral Cdc7 inhibitor, SRA141, demonstrates competitive target selectivity and robust efficacy in several cancer models –
VANCOUVER, Canada I November 13, 2018 I Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with significant unmet needs in hematology and oncology, today reported preclinical data for its novel oral Cdc7 inhibitor, SRA141, in a poster presented at the 30th EORTC-NCI-AACR Symposium currently being held in Dublin, Ireland.
“SRA141 potently and selectively inhibits the cell division cycle kinase, Cdc7, thereby interfering with DNA replication and cell cycle dynamics within tumor cells while sparing normal cells. This unique mechanism results in significant in vitro anti-proliferative activity in a broad spectrum of tumor cell lines derived from both solid and hematologic cancers and translates into robust efficacy in rodent xenograft cancer models,” said Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. “Consistent with the observed anti-cancer activity, a pharmacodynamic assessment reveals potent on-target inhibition in both tumors and surrogate skin tissues, potentially allowing for less invasive monitoring of Cdc7 inhibition in patients.”
“We believe SRA141’s potent and selective in vitro activity, favorable in vivo pharmacokinetic properties and robust anti-tumor efficacy, particularly in colorectal cancer models, competitively positions SRA141 against other Cdc7 inhibitors and supports clinical advancement of the compound,” added Dr. Nick Glover, President and Chief Executive Officer of Sierra Oncology. “Having successfully completed the Investigational New Drug Application (IND) process with the FDA, we have prepared for a first-in-human Phase 1/2 clinical trial of SRA141 to be conducted in metastatic colorectal cancer, an indication of high unmet medical need for which SRA141 has shown considerable promise in preclinical testing.”
As reported in the poster, SRA141:
- Potently and selectively inhibits Cdc7 in in vitro biochemical assays and potently inhibits the phosphorylation of the Cdc7 substrate MCM2 in cells.
- Displays excellent selectivity with less off-target activity than competitive clinical stage Cdc7 inhibitors.
- Displays potent in vitro anti-proliferative activity against several tumor cell lines, including multiple highly sensitive colorectal tumor cell lines, with activity comparable or superior to other Cdc7 inhibitors in the majority of lines tested.
- Demonstrates excellent anti-tumor activity, including complete and partial regressions, in several in vivo tumor models representing solid (colorectal) and hematologic (B myelomonocytic leukemia, AML) cancers.
- Displays good oral bioavailability and favorable pharmacokinetics in vivo, and potent on-target inhibition (MCM2 phosphorylation) in both tumor and skin tissues.
The poster will be presented at on Tuesday, November 13th at 12:00-6:30 pm (GMT).
Title: The novel oral Cdc7 inhibitor, SRA141, demonstrates robust efficacy in preclinical cancer models
Authors: R. Hansen, S. Milutinovic, B. Strouse, M. Hedrick, G. Smith, C. Hassig
About SRA141
SRA141 is a potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). Cdc7, a serine-threonine kinase, is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.
Cdc7, together with its partner proteins Dbf4 or Drf1, is responsible for activating DNA replication during S-phase through phosphorylation and activation of the MCM2-7 helicase. Cdc7 also has functions within the DNA Damage Response (DDR) and mitosis. Over-expression of Cdc7 and its partner proteins is correlated with unfavorable clinical outcomes and poor survival in a broad range of solid tumors and hematological malignancies.
SRA141’s inhibition of Cdc7 has been shown to cause cancer cell death in a p53-independent manner and to induce tumor regression or stasis in a variety of in vivo cancer models, including complete and partial regressions in animal models of colorectal cancer.
Sierra recently reported that the U.S. Food and Drug Administration (FDA) has accepted its Investigational New Drug (IND) application for SRA141. The company plans to conduct a Phase 1/2 clinical trial designed to assess the safety and tolerability of SRA141 in patients with colorectal cancer.
Sierra Oncology retains the global commercialization rights to SRA141.
About Sierra Oncology
Sierra Oncology is a clinical stage drug development company advancing targeted therapeutics for the treatment of patients with unmet medical needs in hematology and oncology. Our lead drug candidate, momelotinib, is a potent, selective and orally-bioavailable JAK1, JAK2 and ACVR1 inhibitor that has been investigated in two completed Phase 3 trials for the treatment of myelofibrosis and has demonstrated a potentially differentiated therapeutic profile encompassing anemia-related benefits, as well as achieving substantive spleen and constitutional symptom control.
Sierra is also advancing SRA737 and SRA141. SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of cell cycle progression and the DNA Damage Response (DDR). SRA737 is currently being investigated in two Phase 1/2 clinical trials primarily focused on patients with ovarian cancer: SRA737-01, a monotherapy study, and SRA737-02, a drug combination study evaluating SRA737 potentiated by low dose gemcitabine. Sierra has also prepared for a potential clinical study of SRA737 in combination with a PARP inhibitor. SRA141 is a Phase 1 ready, potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.
SOURCE: Sierra Oncology
Post Views: 18
