SCIENCE
Leveraging a fully integrated drug discovery and development engine, our team translates our initial, novel concepts through the clinic and beyond.
Drug Discovery And Development Engine
With a robust set of internal discovery tools and capabilities at our Toronto-based R&D hub, we are intently focused on translating innovative scientific ideas and therapeutic targets into practice-changing medicines. Our in-house drug discovery and development engine continues to reveal promising targets and programs, even as we advance our clinical candidates.
Many of our screening approaches originated from our scientific co-founders. They include multiple large-scale, functional genomics screenings that have uncovered the novel targets we are pursuing.
Our toolbox includes:
We use RNAi libraries consisting of the entire druggable genome to screen for novel targets in a number of contexts. These libraries have been leveraged in the past to uncover PLK4 and TTK: the targets of our most advanced clinical candidates.
Using a cDNA Open Reading Frame library, we overexpress ~4000 distinct cell surface proteins in genetically modified tumor cell lines, in efforts to rescue a particular deficiency in these cells.
Through careful phenotypic analysis of knockout mice,
several novel therapeutic targets have emerged, including a novel immune-oncology target that forms the basis of our most advanced undisclosed antibody program.
By screening the serum of cancer patients for autoantibodies, we can rapidly and efficiently identify fully human antibodies against well-characterized or underappreciated targets.
We use this platform to identify TCRs that go beyond conventional A*02:01 restriction, potentially expanding the addressable patient population with this modality. We have identified two non-A2 TCRs, as well as validated their structural and functional avidity.
We leverage a number of other tools designed to identify novel targets relevant to many pathways that are deregulated in cancer, such as p53, PTEN and NF-kB. These include Packaging Rescue, Drosophila Modifier Enhancer Screens and CRISPR-based technologies.
Novel Targets
Harnessing the power of our drug discovery and development engine, we are able to generate novel oncology targets – all of which have been under-explored in the industry. We are focused on targets that can exploit tumor-specific vulnerabilities as well as novel immuno-oncology targets.
PLK4
PLK4 (polo-like kinase 4) is an enzyme necessary for cancer cells to divide and multiply in the presence of increased chromosome count and is a key regulator of centriole duplication. PLK4 is frequently overexpressed in cancer cells and is associated with adverse survival outcomes. Inhibition of PLK4 has been shown to exacerbate genomic instability in cancer cells, forcing cell death.
We are currently advancing CFI-400945, a small molecule PLK4 inhibitor, in multiple clinical trials. The agent has shown evidence of monotherapy efficacy in solid and liquid tumors.
TTK
TTK (tyrosine threonine kinase) is a critical component of the spindle assembly checkpoint (SAC), a complex signal transduction cascade that regulates mitosis. By targeting TTK in this way, cancer cells, which tend to have SAC dysfunction, are forced prematurely into the next phase of the cell cycle and could lead to segregation errors, increased aneuploidy and cell death. High expression of TTK correlates with poor patient outcomes.
We are currently advancing CFI-402257, a small molecule TTK inhibitor, for the treatment of ER+ breast cancer.
HPK1
A pleiotropic negative regulator of immune cell activation, inhibition of HPK1 (hematopoietic progenitor kinase 1) has been shown to activate T cells, B cells and dendritic cells.
We are currently investigating CFI-402411, a small molecule HPK1 inhibitor, with a focus on solid tumors as a monotherapy or in combination with pembrolizumb. HPK1 represents a unique small molecule immuno-oncology target.
While pursuing these early successes, our research continues to identify previously unexplored targets of therapeutic intervention for the most aggressive of cancers.
We are also developing a novel approach to autologous, TCR transgenic, T-cell therapies through our robust internal TCRypt platform. Using this tool, we can identify therapeutically relevant TCRs for therapies in a rapid, high-throughput manner. We believe our approach can address patient populations underserved by current approaches in a variety of different solid and hematologic malignancies where there is an unmet need.
In addition, we are advancing a number of internally developed biologic programs that represent novel immuno-oncology targets.
For more information on our small molecule, TCR cell therapy and biologic programs in development, please visit our Pipeline page.
Publications and Presentations
Targeting Mitosis in Cancer: Emerging Strategies
Carmen Dominguez-Brauer, Kelsie L. Thu, Jacqueline M. Mason, Heiko Blaser, Mark R. Bray…
Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial
Zachary W. Veitch, David W. Cescon, Trisha Denny, Lisa-Maria Yonemoto, Graham Fletcher…
Functional Characterization of CFI-400945, a Polo-like Kinase 4 Inhibitor, as a Potential Anticancer Agent
Jacqueline M. Mason, Dan Chi-Chia Lin, Xin Wie, Yi Che, Yi Yao…
Functional Characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer
Jacqueline M. Mason, Xin Wei, Graham C. Fletcher, Reza Kiarash, Richard Brokx…