Novel Synthetic Mechanism to b-Lactone and Analogs: Lead Compounds for the Treatment of Proteasome-Related Diseases
Summary Background: Proteasome inhibition offers considerable promise in the therapy of a number of types of diseases, such as cancer and neurodegenerative diseases. One such proteasome inhibtor, Velcade, is currently marketed for treatment of multiple myeloma by Millennium Pharmaceuticals. Despite the success of Velcade, there still exist many issues to resolve. For example, animal studies indicated that bortezomib injected intravenously leaves the vascular compartment within minutes, rendering correlations between plasma concentrations and proteasome inhibition, drug toxicity, and clinical activity difficult Moreover, after intravenous injection, bortezomib is widely distributed in tissues but does not gain access to privileged sites such as the brain, spinal cord, eyes, and testes. Dose-limiting toxicity (DLTs) studies indicated both diarrhea and sensory neuropathy as side effects.
A new proteasome inhibitor recently identified is lactacystin. Lactacystin, a proteasome inhibitor isolated from Streptomyces lactacystinaeus initially drew interest based on its ability to induce differentiation of neuroblastoma cells and to inhibit cell cycle progression. Mechanistic studies have also established that lactacystin inhibits the proteasome through the 20S proteasome, the proteolytic core of the 26S proteasome. The biological activities of lactacystin, the scarcity of natural materials and challenging chemical structures of the molecules have stimulated synthetic efforts directed toward lactacystin and related analogs. However, the various synthesis pathways of lactacystin that are reported are lengthy, result in low yield and none are particularly suited for analog synthesis.
Invention: A novel synthetic mechanism to lactacystin and analogues. The synthetic platform to clasto-lactacystin and analogs proceeds in fewer steps and in much greater overall yield than methods described in prior art. One lead analog, clasto-Lactocystin b-lactone demonstrates strong efficacy and is a lead candidate for treatment of stroke and related brain injuries.
Phase I Clinical Study: The safety, tolerability, and pharmacodynamics of the lead analog in young male volunteers was assessed. A bolus injection was administered to healthy male volunteers as single and repeated doses up to 1.6 mg m-2. The study was double blind, randomized, and placebo-controlled. There was no significant effect on blood pressure or heart rate (including ECG) during the trial. No significant abnormalities in biochemistry, haematology, or urinalysis were identified. 28% of the active group reported minor adverse events such as altered taste sensation and discomfort in the injection arm post-dosing, but these were later determined to be not drug dose related. Importantly, proteasome inhibition as measured by blood 20S assay achieved the maximum target level of 70-80% with 1.6 mg m-2.
Applications Lactacystin and its analogs my be used to treat conditions mediated directly by the proteolytic function of the proteasome, such as muscle wasting, or mediated indirectly via proteins which are processed by the proteasome such as NF-kB. Specific examples are as follows:
-Alzheimers disease: It is believed that abnormal protein processing by the proteasome contributes to the abundance of b-AP in the Alzheimerâ€™s brain. The administration to an Alzheimer patient b-lactam analogs to reduce the rate of b-AP processing would reduce the rate of b-AP plaque formation, thus attenuating the clinical signs of Alzheimers disease.
-Muscle Wasting Diseases (Cachexia): The proteasome degrades many proteins in maturing reticulocytes and growing fibroblasts. In cell deprived of insulin or serum, the rate of proteolysis nearly doubles. Inhibiting the proteasome reduces proteolysis, thereby reducing both muscle protein loss and the nitrogenous load on kidneys or liver.
-Regulation of Cyclins: Cyclins are proteins involved in cell cycle control. The proteasome participates in the degradation of cyclins. Degradation of cyclins enables a cell to exit one cell cycle stage (mitosis) and enter another (division). Inhibition of the proteasome inhibits cyclin degradation and therefore inhibits cell proliferation.
-Cancer: Millennium pharmaceuticals lead proteasome inhibitor Velcade (see Market below) is currcell lymphoma, and phase II clinical trials for patients with follicular or marginal zone lymphoma and non small cell lung cancer.
Market: The only FDA approved proteasome inhibitor drug is Millennium Pharmaceuticals VelcadeÂ®. In 2004, U.S. sales of VELCADE for multiple myeloma alone were approximately $143.1 million and rising. There are two other proteasome inhibitors in clinical trials. The first is in a phase I trial with PR-171 for treatment of multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease. The second is also in phase I clinical trials (PS341) for treatment of HER2 positive metastatic breast cancer patients The annual new cases each of cancer totals more than 1,248,900 annually patients. 4.5 million cases of Alzheimersâ€™ disease were diagnosed last year, while the prevalence of Alzheimer's is expected to increase to 11.3-16 million cases in America by
6,335,358 6,214,862 6,147,223 5,756,764
Williams A.J. et al. Delayed treatment of ischemia/reperfusion brain injury: extended therapeutic window with the proteosome inhibitor MLN519. Stroke. 2004 May; 35(5):1186-91.
Schreiber, Stuart L.
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