Myelosuppression is a common complication of cancer treatment that limits the efficacy of conventional chemotherapy. It has been demonstrated that inhibiting glutathione S-transferase (GST)isozyme P1-1 in animals results in myelostimulation analogous to the action of the recombinant colony-stimulating factor G-CSF. This Phase I SBIR project will identify GSTP1-1 inhibitors that are more potent and isozyme-specific than competing inhibitors, by employing a novel structural motif in the proposed compound libraries. Screening of the libraries will be performed using an innovative and proprietary chip technology that will allow large repertoires to be synthesized and screened more easily, and with throughputs significantly better than currently available combinatorial methods. Preliminary experience with the chip technology and with model compounds suggests feasibility will be demonstrated for the chip screening technology and the proposed structural motif. Feasibility in Phase I will provide the basis for scale-up of screening and biologic testing in Phase II. Low-molecular weight GSTP1-1 inhibitors identified in Phase II that are both highly potent and isozyme-specific may lead to oral myelostimulants for treating myelosuppression during cancer therapy.
An oral myelostimulant will capture a significant portion of the market for """"""""injection-only"""""""" factors by providing an oral substitute. The current market for recombinant factors is over $1 billion. The chip libraries will have commercial potential in the $50M research market related to drug discovery tools as """"""""off-the-shelf"""""""" libraries. Market penetration of products will be achieved through joint ventures with established corporations.
| Maeda, Dean Y; Mahajan, Sumit S; Atkins, William M et al. (2006) Bivalent inhibitors of glutathione S-transferase: the effect of spacer length on isozyme selectivity. Bioorg Med Chem Lett 16:3780-3 |
