Onconova's Library of New Chemical Entities
The Onconova chemical library has over 125 unique chemotypes. Progress in identifying novel active and selective agents for several molecular targets is summarized below.
In addition to evaluating our small molecule active compounds in biochemical, cell-based and whole animal models, the Company has used certain of our anti-cancer compounds to prepare antibody-drug conjugates (ADCs). Further information about our pre-clinical programs is provided below.
Bcr-Abl/JAK2 Inhibitors:
New class of dual kinase inhibitors
Recently, many hematological diseases have been shown to have a molecular defect in regulation of Janus Kinase 2 (JAK2), a tyrosine kinase involved in signal transduction, resulting in JAK2 over-expression. This enzyme is believed to be an excellent molecular target for pharmacological intervention in polycythemia vera and several other chronic and proliferative disorders.
The Philadelphia Chromosome translocation gene, Bcr-Abl, dramatically over-expresses the Abl tyrosine kinase function and is associated with certain leukemias, particularly chronic myelogenous leukemia (CML). The first marketed selective Bcr-Abl kinase inhibitor, imatinib, has been an effective agent for treating CML, gastrointestinal stromal tumors (GISTs) and a number of other cancers. It acts by competing with ATP at the kinase active site. Unfortunately, imatinib resistance due to mutations in the Bcr-Abl target protein has emerged.
Onconova has screened its library for selective Bcr-Abl inhibitors that are not ATP competitors. Several potent compounds in the ON 04 chemotype series have been identified, including those that also inhibit imatinib-resistant mutant Bcr-Abl kinase proteins.
A few of these ON 04 compounds have displayed an interesting dual inhibition activity against both Bcr-Abl and the JAK2 kinase. ON 044580 is the most advanced compound in this series. Key features:
- Non-ATP competitive compounds
- New enzyme inhibition spectrum
- Potential for oral and injectable formulations.
Anti-Tubulin Agents:
Causing tubulin depolymerization
Tubulin is an essential structural protein of the mitotic spindle that forms during cell division. Tubulin inhibitors prevent the cell division process and can be effective anti-tumor agents, such as taxanes and certain alkaloids. Onconova has discovered compounds in its library that depolymerize (de-stabilize) tubulin spindles, thus stopping mitosis. Members of the ON 24 chemotype series are being evaluated in cell-based tests and whole animal models. The most advanced anti-tubulin agent is ON 24160, which has been shown to depolymerize β-tubulin.
HER2 Inhibitors
Human Epidermal Growth Factor Receptor 2 (HER2) is a protein correlated with aggressiveness in breast cancers and a validated target for anti-tumor intervention. Approximately 20% of breast cancers have an amplification of the gene or overexpression of its protein product. HER2 is a cell membrane receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. Onconova is investigating members of the ON 04 chemotype series as selective inhibitors of HER2 kinase. The most advanced candidate is ON 045270, which is non-ATP-competitive inhibitor.
CDK4 Inhibitors
Cyclin-dependent kinase 4 (CDK4) is part of the cyclin-dependent kinase family. The protein encoded by this gene is a member of the Serine/Threonine protein kinase family. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb, were all found to be associated with tumorigenesis of a variety of cancers.
Onconova is investigating members of the ON 123 chemotype series as selective inhibitors of CDK4. The most advanced candidate is ON 123300, which is an ATP-competitive inhibitor.
Immunoconjugate Technology:
Improving therapeutic activity of anti-cancer monoclonal antibodies
Immunoconjugates are antibody proteins conjugated to a second molecule, usually a drug, toxic agent or radioisotope. These conjugates are used as a targeted form of chemotherapy. Novel molecules suitable for use in immunoconjugates, i.e., antibody-drug conjugates (ADCs), are being developed as a resource for companies developing this class of drugs. These molecules are derived from our portfolio of highly potent small molecule inhibitors targeted to the regulation of the cell cycle, signal transduction and other important regulatory networks.
These potent inhibitors are converted to pro-drug molecules that contain two key elements:
- A linkage site for attachment to monoclonal antibodies (MoAbs) and other therapeutic proteins;
- A variable linker designed to efficiently release the drug molecule inside targeted malignant cells.
These pro-drug molecules are particularly well-suited for use with MoAbs that are internalized by cancer cells upon binding to tumor-specific cell surface antigens. The effectiveness of this approach depends upon careful design of the linker (ensuring stability in the circulation, efficient intracellular release, and ease of manufacture). Since many of our potent compounds overcome the inherent limitations of other drugs previously used for immunoconjugates (i.e., drug resistance, adequate potency, and suitable therapeutic index), the present approach has yielded ADCs with broader efficacy and higher margins of safety.