Increased prostate cancer (PCa) cell motility drives invasion out of the prostate gland, promoting the formation of metastasis. For established metastatic lesions, it promotes both further invasion into, and destruction of, critical end organs. If PCa cell motility could be therapeutically inhibited, it would have a major clinical impact. For those with metastatic disease, it would inhibit destruction of critical end organs, and the development of secondary metastasis. For those with high risk localized PCa, it would augment local therapy by inhibiting initial development of metastasis from residual local disease and by inhibiting pre-existing micrometastatic disease from invading into critical organs and from spawning secondary metastasis. For those with intact prostate glands, it would inhibit local invasion into and destruction of bladder and urinary outflow function. In all scenarios, inhibition of cell motility would lead to prolongation of life, improvement of its quality, and would augment existing therapeutic modalities. It has been a major challenge to discover drugs that selectively inhibit PCa cell motility. Focusing on this, our group has identified pathways that regulate human PCa cell motility, and has therapeutically targeted them in preclinical models and in prospective human trials. The phase II study was published in JNCI and represents the first study in which prometastatic pathways in humans were successfully targeted, for any cancer type. Although our work was comprehensive and bench-to-clinic translational, we believe the pathways identified and the natural product therapeutic employed, both lacked adequate selectivity (a common problem in this field). We therefore undertook a de novo innovative discovery approach, yielding KBU2046, a highly selective and potent small molecule that inhibits human PCa metastasis in mice at low nM concentrations after oral delivery. KBU2046’s mechanism of action is inhibition of phosphorylation of Ser226 on heat shock protein 90β, and is novel and selective for inhibition of cell motility. Comprehensive pharmacokinetic and toxicology testing support the notion that KBU2046 will be an effective therapeutic in humans. Our objective is move KBU2046 into clinical trials. Our current goals are: i. to develop the processes for cGMP scale-up synthesis; ii. to conduct toxicology profiling under GLP conditions, iii. to define the efficacy of KBU2046 in combination with chemotherapy in systemic models, and iv. to submit an IND.
|Effective start/end date
|9/30/15 → 8/31/18
- Oregon Health and Science University (1007494_NWU // W81XWH-15-1-0527)
- U.S. Army Medical Research and Materiel Command (1007494_NWU // W81XWH-15-1-0527)
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