Activated Checkpoint Therapy® Platform
ArQule’s Novel Approach to Cancer: Activated Checkpoint Therapy® (ACT) Platform
ArQule’s lead approach to cancer therapy development is intended to restore and activate cellular checkpoints through the use of small-molecule drugs. In contrast to conventional chemotherapy approaches, ArQule’s Activated Checkpoint Therapy® (ACT) platform is designed to be selective for cancer cells. By activating checkpoint functions without damaging DNA, drug candidates based on the ACT platform are intended to cause the selective demise of cancer cells, while sparing normal cells. The intended result is improved efficacy and reduced toxicity. Further, compounds resulting from the ACT platform are designed to apply to a broad spectrum of cancers and counteract cancer heterogeneity.
| Chemotherapy | ACT Platform Goals | |
|---|---|---|
| Principle Objective | Damage of DNA in cancer cells | Restore and activate checkpoints |
| Effect on normal cells | DNA damage | No DNA damage |
| Result | Toxicity to both cancer cells and normal cells | Reduced toxicity to normal cells |
ArQule's Biomedical Institute has initiated a series of research and drug discovery programs designed to identify novel targets within checkpoint pathways and exploit the Company's chemistry capabilities to discover and develop novel drugs targeting checkpoint pathways. The first of these, a small molecule known as ARQ 501, targets the E2F1 pathway. In vitro and in vivo preclinical studies with this compound provided proof of principle of the ACT approach. Phase 1 clinical trials have been completed with ARQ 501, and a Phase 2 clinical program has been initiated.
ARQ 501 is the Company's most advanced ACT candidate and is partnered with Roche. GLP toxicology studies have been initiated with a second-generation E2F1 compound generated from this program, ARQ 171.
ArQule is also applying the ACT-based drug discovery approach to screen for compounds that directly activate additional candidate checkpoints without first inducing DNA damage or disrupting microtubule (cell skeleton) dynamics. Candidate compounds from this program are in pre-clinical development.
An Overview of the Activated Checkpoint Therapy® Platform
A checkpoint is a cell's natural defense mechanism that ensures genomic integrity. Depressed checkpoint function is a hallmark of cancer cells. In the normal cell cycle, checkpoints allow cells to repair DNA damage or to undergo apoptosis (programmed cell death). Cancer cells, with multiple abnormalities including genetic (DNA) damage, survive and proliferate because key checkpoints and apoptotic pathways are disabled during development of cancer. Conventional chemotherapy seeks to kill cancer cells by creating further damage to DNA. A well-known side effect of this approach is that normal cells are indiscriminately damaged, creating toxicity to patients and limiting the effectiveness of chemotherapy. Furthermore, the depressed checkpoint pathways limit cancer cell killing activity of conventional chemotherapy.
ArQule’s unique approach to cancer therapy is designed to restore or reactivate checkpoint functions that are lost in cancer cells. The Company develops small molecules designed to activate cell cycle checkpoint functions within cancer cells, allowing them to detect and respond to DNA damage. As a result, cancer cells proceed toward apoptosis. This approach, the Activated Checkpoint Therapy® platform, is a key concept in ArQule’s approach to drug development.
Background on Checkpoints
Human beings are made up of billions of cells that grow and divide. The process that brings about the reproduction of cells is called the cell cycle. The cell cycle is divided into a number of distinct phases. Normal, non-proliferating cells exist in the phase known as G0. In G1 phase, the cell increases in size and begins to produce the molecules required for DNA replication. The process of DNA replication occurs in S-phase. Following a second preparatory phase, called G2, the cell initiates the process of mitosis, or M phase, eventually forming two daughter cells. An important point in the cell cycle occurs at the restriction point, where the cell commits itself to completing the cell cycle. In addition to the restriction point, there are other points along the cell cycle, called checkpoints, in which cells check on the integrity of the DNA and other key structural components to ensure proper progression of the cell cycle.
At the molecular level, the cell cycle is a complex process that is controlled by a vast network of biochemical pathways within cells. These pathways become deregulated in cancer cells, resulting in abnormal cell proliferation and accumulation. As a result, cancer cells undergo cell division in an uncontrolled way. Virtually all cancer cells have major defects in apoptosis and cell cycle pathways.
Checkpoints are Disabled in Cancer Cells
Apoptosis is a normal cellular function designed to kill cells, thus protecting the organism, in the event of acquired mutations. The program begins with the activation of cell cycle checkpoints that detect and respond to acquired abnormalities, or mutations, in DNA. Upon detection of irreparable DNA damage, cells with intact checkpoints proceed toward apoptosis. Cells undergoing apoptosis die according to a pre-programmed sequence of biochemical events inside the cell. During this process, the cell’s internal machinery is turned to its own destruction through activation of a family of intracellular enzymes that digest the cell from the inside out with great efficiency. While apoptosis is fatal to the cell, the process protects the organism as a whole by preventing the formation and accumulation of cancer cells.
Checkpoint Activation as Strategy Against Cancer
If the cell cycle is the production line that drives the cell replication process, checkpoints are the quality control functions, ensuring that cells reproduce with intact DNA. If the quality control function is disabled, cells can continue to replicate even if there are major defects present in their DNA.
What would happen if one were to suddenly re-activate the quality control process in a cancer cell? Theoretically by re-activating the quality control, or checkpoint functions of a cell, an agent would allow the cell to detect and respond to DNA damage. Cancer cells contain constitutive oncogene activation and irreparable DNA derangements. Consequently, one would expect to see apoptosis of a large number of cancer cells.
Checkpoint Activation Results in Selectivity
Of equal importance is the effect of checkpoint activation in normal cells. Normal, healthy cells have little DNA damage compared with cancer cells. Consequently, when a checkpoint is activated in a healthy cell, one would expect to see no apoptosis. In other words, since non-cancer cells are genetically normal, they should be spared even if exposed to the same checkpoint-activating stimulus as the cancer cell.
Sparing normal cells while killing cancer cells forms the basis for selectivity in ACT-based therapy. Lack of selectivity is the main reason that conventional chemotherapy fails. Based on research performed to date, ArQule believes that ACT-based therapy has the potential to offer improved efficacy and reduced toxicity over traditional chemotherapies.