Sierra Oncology’s Cancer Therapies Target the DNA Damage Response Network

Sierra Oncology is a clinical stage drug development company advancing targeted DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer.

The company’s lead drug candidate, SRA737, is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by oncogenes (e.g., MYC and RAS) combined with loss of function in tumor suppressors (e.g., p53 and ATM) results in persistent DNA damage and genomic instability.

Targeted inhibition of the remaining components of the DDR network such as by SRA737 may be synthetically lethal to cancer cells and have utility as a monotherapy in a range of tumor indications. Chk1 is also believed to facilitate tumor cell resistance to chemotherapy or radiation-induced DNA damage and the combination of SRA737 with these standards-of-care may provide synergistic anti-tumor activity. SRA737 is currently being investigated in two Phase 1 clinical trials in patients with advanced cancer.

Sierra Oncology is also advancing SRA141, a potent, selective and orally bioavailable small molecule inhibitor of the Cdc7 kinase undergoing preclinical development. Cdc7 is a key regulator of both DNA replication and the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.

The DNA Damage Response (DDR) network is a system of cellular pathways that monitor and repair DNA damage in an effort to maintain genomic integrity throughout the cell cycle.

Several proteins within the DDR network govern key transitions between the phases of the cell cycle and are collectively known as cell cycle checkpoints components. The DDR network can activate these cell cycle checkpoints, to temporarily pause cellular replication in order to facilitate the repair of damaged DNA.

In cancer cells lacking the G1/S checkpoint, targeted inhibition of the remaining components of the DDR network may be synthetically lethal to cancer cells compared to normal cells, and therefore of potential benefit in the treatment of certain cancers. Specifically, by inhibiting critical S or G2/M cell cycle and DNA replication checkpoint components, such as Chk1 and Cdc7, cancer cells may be rendered unable to repair their damaged DNA, and subsequently driven into a catastrophic replicative process ultimately resulting in cell death.

Many standard chemotherapeutic agents and radiotherapy also induce DNA damage and may be synergistic with Chk1 and Cdc7 inhibitors. Sierra’s lead drug candidate, SRA737 is a small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network.

The oral bioavailability of SRA737 affords greater dosing flexibility for both monotherapy and combination therapy settings than is possible with intravenously administered agents. SRA737 is currently being investigated in two Phase 1 clinical trials in patients with advanced cancer:

Monotherapy – Targeting inhibition of the remaining components of the DDR network with SRA737 may be synthetically lethal to cancer cells and have utility as a monotherapy in a range of tumor indications. In this trial, we plan to exploit synthetic lethality in patients with genetically defined tumors that harbor genomic alterations hypothesized to confer sensitivity to Chk1 inhibition.

Chemotherapy – Chk1 is believed to facilitate tumor cell resistance to chemotherapy or radiation-induced DNA damage. The combination of SRA737 with gemcitabine and gemcitabine/cisplatin may provide synergistic anti-tumor activity, consistent with findings in preclinical oncology models.

For more information, please visit the company’s website.