BI811283
Encyclopedia
BI 811283 is a small molecule
inhibitor
of the Aurora B kinase
protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. BI 811283 is currently in the early stages of clinical development and is undergoing first in human trials in patients with solid tumors and Acute Myeloid Leukaemia
.
binding pocket of the Aurora B Kinase protein, inhibiting its function in cell division
. The Aurora B kinase protein (also known as STK12) is one of a family of protein
s that plays an essential role in the alignment, movement and separation of chromosome
s during cell division
. Aurora B kinase is produced in all dividing cells in normal tissue however; the levels of Aurora B kinase are abnormally raised in many types of cancer
. Abnormally elevated levels of Aurora B kinase, cause unequal chromosomal separation during cell division, resulting in the formation of cells with abnormal numbers of chromosomes
, which are both a cause and driver of cancer.
Inhibition of Aurora B kinase by BI 811283 in cancer cells leads to the formation of cells with severely abnormal numbers of chromosomes (polyploid). Counterintuitively, inhibition of Aurora B kinase by BI 811283 actually causes the polyploid cells formed to continue dividing however, because these cells have severe chromosomal abnormalities, they eventually stop dividing or undergo cell death.
, head and neck
, colorectal
and ovarian cancer
, where it is associated with worse treatment outcome and poorer overall survival.
Further phase 1 and 2 trials are underway investigating the use of BI 811283 in patients with different types of advanced solid tumours and Acute Myeloid Leukaemia.
s. BI 811283 has been developed to selectively target dividing cells, therefore reducing the severity of adverse effects experience by patients. The most common and severe side effect
experienced with BI 811283 is a reduction in the number of white blood cell
s (leucopenia and neutropenia
) which occurs in between 17-42% of patients and can increase the risk of infection
s and fever
.
have demonstrated that BI 7811283 selectively binds to and inhibits the Aurora B kinase protein leading to inhibition of growth and senescence
in lung cancer
cells in vitro
. Furthermore, BI 811283 also inhibits the growth of pancreatic
, colorectal and non-small cell lung cancer cells in vivo
leading to tumour shrinkage.
First in man clinical trial
s have demonstrated that BI 811283 is safe and stable in the blood stream. Two early clinical trials have reported that BI 811283 has anti-tumour activity, preventing the progression of cancer in between 29-33% of patients with advanced solid tumours.
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
inhibitor
Inhibitor
Something that restrains, blocks, or suppresses.Inhibitor or inhibition may refer to:* Corrosion inhibitor, a substance that decreases the rate of metal oxidation...
of the Aurora B kinase
Aurora B kinase
Aurora B kinase is a protein that functions in the attachment of the mitotic spindle to the centromere.In cancerous cells, over-expression of these enzymes causes unequal distribution of genetic information, creating aneuploid cells, a hallmark of cancer....
protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. BI 811283 is currently in the early stages of clinical development and is undergoing first in human trials in patients with solid tumors and Acute Myeloid Leukaemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
.
Mechanism of action
BI 811283 is a small molecule drug that selectively binds to the ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
binding pocket of the Aurora B Kinase protein, inhibiting its function in cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
. The Aurora B kinase protein (also known as STK12) is one of a family of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that plays an essential role in the alignment, movement and separation of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s during cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
. Aurora B kinase is produced in all dividing cells in normal tissue however; the levels of Aurora B kinase are abnormally raised in many types of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Abnormally elevated levels of Aurora B kinase, cause unequal chromosomal separation during cell division, resulting in the formation of cells with abnormal numbers of chromosomes
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
, which are both a cause and driver of cancer.
Inhibition of Aurora B kinase by BI 811283 in cancer cells leads to the formation of cells with severely abnormal numbers of chromosomes (polyploid). Counterintuitively, inhibition of Aurora B kinase by BI 811283 actually causes the polyploid cells formed to continue dividing however, because these cells have severe chromosomal abnormalities, they eventually stop dividing or undergo cell death.
Clinical Uses
BI 811283 is currently undergoing investigation in phase 1 and 2 trials and has yet to be licensed by the FDA. BI 811283 may be active in a range of malignancies that are known to have raised levels of Aurora B kinase including; non-small cell lung, brainBrain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
, head and neck
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
, colorectal
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
, where it is associated with worse treatment outcome and poorer overall survival.
Further phase 1 and 2 trials are underway investigating the use of BI 811283 in patients with different types of advanced solid tumours and Acute Myeloid Leukaemia.
Adverse Effects
Traditional anti-cancer agents that block cell division commonly cause severe adverse effectAdverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s. BI 811283 has been developed to selectively target dividing cells, therefore reducing the severity of adverse effects experience by patients. The most common and severe side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
experienced with BI 811283 is a reduction in the number of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s (leucopenia and neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
) which occurs in between 17-42% of patients and can increase the risk of infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
.
Studies
Pre-clinical studiesPre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
have demonstrated that BI 7811283 selectively binds to and inhibits the Aurora B kinase protein leading to inhibition of growth and senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
in lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
cells in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. Furthermore, BI 811283 also inhibits the growth of pancreatic
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, colorectal and non-small cell lung cancer cells in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
leading to tumour shrinkage.
First in man clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s have demonstrated that BI 811283 is safe and stable in the blood stream. Two early clinical trials have reported that BI 811283 has anti-tumour activity, preventing the progression of cancer in between 29-33% of patients with advanced solid tumours.