THE LEUCHEMIX PIPELINE

LC-913 Series
These agents are novel antileukemic currently licensed and being developed by the company.
The lead compound has shown excellent pre-clinical activity in a broad range of hematological malignancies ranging from AML, ALL, CLL to Lymphoma. Additionally, it has been demonstrated to synergize with a variety of clinically used agents in pre-clinical models of prostate, breast, bladder, and lung cancer. Leuchemix is currently completing all pre-clinical studies in anticipation of a regulatory filing for human testing in 2006 in Acute Myelogenous Leukemia, followed by additional trials.

LC812 Series
Other pre-clinical studies under development at Leuchemix represent extensions of the platforms of natural product chemistry and tumor biology licensed by the company. They represent an example of both natural product adaptation and de novo synthesis of anti-tumor agents. We have continued to exploit the cytotoxic nature of a variety of natural products and we have a series of derivatives that are entering pre-clinical investigation. The activity of the lead member of this series against a number of hematological disorders has been demonstrated, and we are determining which compound should be advanced into pre-clinical development.

LCVJ Series
Microtubules are involved in a number of cellular functions, such as motility, division, shape maintenance, and intracellular transport. The major protein component found in microtubules is tubulin. Interference with microtubule assembly, either by inhibition of tubulin polymerization or by blocking microtubule disassembly, leads to an increase in the number of cells in metaphase arrest. Inhibition of microtubule function using tubulin targeting agents is a validated approach to anticancer therapy.

Examples of clinically used antimitotic agents are derived from natural sources vincristine (I) and colchicine (II). One of the structural entities in the vincristine molecule is the indole nucleus, which is a core structural component in great number of tubulin polymerization inhibitors.



Synthetic molecules containing an indole nucleus have also been reported as tubulin inhibitors. As such, we have licensed a broad variety of molecules based on this foundation and have discovered potent antitumor effects in both the leukemic and solid tumor states. The LCVJ series is being actively pursued in leukemic and other diseases.

LCVJ2 series
Combretstatins are mitotic agents isolated from the bark of the South African tree Combretum caffrum. The most potent of these is combretastatin A-4 (I), which has been found to be potent cytotoxic agent and which strongly inhibits the polymerization of brain tubulin by binding to the colchicines site. Also, combretastatin A-4 shows potent cytotoxicity against a wide variety of human cancer cell lines including MDR cancer cell lines.



Combretastatin A-4 is thus lead compound for development of anticancer drugs and a variety of pharmaceutical companies are pursuing these anticancer agents. We have licensed a series of compounds that have been synthesized ‘de novo’ and share similar activities with the combretastatins and have potent antitumor activity against a broad range of tumor types.