- Compelling preclinical data for its Cdc7 inhibitor, SRA141, indicate a potentially novel and distinct mechanism of action -
VANCOUVER, April 3, 2019 /PRNewswire/ - Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with unmet needs in hematology and oncology, reported preclinical data for its novel oral Cdc7 inhibitor, SRA141, in a late-breaking poster being presented today at the American Association of Cancer Research (AACR) Annual Meeting 2019 in Atlanta, Georgia.
"Prior studies demonstrated that SRA141 potently and selectively inhibits Cdc7, resulting in robust anti-tumor efficacy in colorectal xenograft models, however, the compound's exact mechanism of action has not been characterized previously. Our findings reveal a potentially novel mechanism of cytotoxicity for Cdc7 inhibitors that is distinct from other agents, and thus SRA141 may herald a new class of cancer therapeutic agents with a differentiated anti-tumor profile," said Dr. Eric J. Brown, Associate Professor of Cancer Biology at the Perelman School of Medicine of the University of Pennsylvania, and member of Sierra's DNA damage response (DDR) Advisory Committee.
"SRA141 does not induce G1 cell cycle arrest or replication stress, thereby distinguishing it from other agents such as palbociclib or SRA737. Rather, SRA141 alters DNA replication dynamics and delays cell cycle progression, ultimately resulting in caspase-dependent cell death associated with mitotic accumulation. Promisingly, we believe we have shown for the first time that this mechanism appears to synergize with anti-apoptotic drugs, such as venetoclax, and dysregulators of mitosis, such as barasertib. This differentiated mechanism of action supports a potentially unique spectrum of clinical opportunities for SRA141 as both monotherapy and in combination with pro-apoptotic and mitotic disrupting agents," said Dr. Christian Hassig, Chief Scientific Officer, Sierra Oncology.
SRA141 AACR Late-Breaking Poster:
Date/Time: Wednesday, April 3rd from 8:00 am to 12:00 pm ET
Session: Late-Breaking Research: Molecular and Cellular Biology / Genetics 2
Title: CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics.
Authors: Veena Jagannathan, Snezana Milutinovic, Ryan J. Hansen, Bryan Strouse, Christian Hassig and Eric J. Brown.
Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 41, Poster #5
The poster will be made available on the company's website at www.sierraoncology.com.
About SRA141 targeting Cdc7
SRA141 is a novel, potent, orally bioavailable selective inhibitor of Cell division cycle 7 (Cdc7) kinase. Owing to its important role in DNA replication, and its overexpression in various neoplasms, Cdc7 is an attractive therapeutic target with emerging clinical validation in oncology.
Cdc7, together with its partner proteins Dbf4 or Drf1, is responsible for activating DNA replication origin firing 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 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.
An Investigational New Drug Application (IND) filing has been accepted by the U.S. Food and Drug Administration (FDA) for SRA141, and Sierra Oncology has prepared for a potential Phase 1/2 trial of the drug candidate in patients with advanced colorectal cancer. Sierra Oncology is currently evaluating the optimal timing to commence this trial within the context of its recently expanded portfolio.
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 splenic volume reduction and constitutional symptom control.
Sierra Oncology 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 non-cytotoxic low dose gemcitabine. Sierra Oncology has also prepared for a potential clinical study of SRA737 in combination with a PARP inhibitor. SRA141 is a 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.
For more information, please visit www.sierraoncology.com.
Cautionary Note on Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Sierra Oncology's market and industry position, expectations from current data, anticipated clinical development activities and timing and potential benefits of Sierra Oncology's product candidates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements. Such forward-looking statements are subject to risks and uncertainties, including, among others, the risk that Sierra Oncology may be unable to successfully develop and commercialize product candidates, product candidates may not demonstrate safety and efficacy or otherwise produce positive results, Sierra Oncology may experience delays in the preclinical and anticipated clinical development of its product candidates, Sierra Oncology may be unable to acquire additional assets to build a pipeline of additional product candidates, Sierra Oncology's third-party manufacturers may cause its supply of materials to become limited or interrupted or fail to be of satisfactory quantity or quality, Sierra Oncology's cash resources may be insufficient to fund its current operating plans and it may be unable to raise additional capital when needed, Sierra Oncology may be unable to obtain and enforce intellectual property protection for its technologies and product candidates and the other factors described under the heading "Risk Factors" set forth in Sierra Oncology's filings with the Securities and Exchange Commission from time to time. Sierra Oncology undertakes no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof, other than as may be required by applicable law.
SOURCE Sierra Oncology