New Paradigm for Development
Peter Ulrich, Ph.D., is cofounder and CEO of TargeGen (www.targegen.com), a company that specializes in therapeutics against vascular leakage, a condition that contributes to about 20 major diseases including wet AMD and pulmonary edema.
TargeGen teamed up with David Cheresh, M.D., professor of pathology at UCSD’s Moores Cancer Center, to capitalize on small molecule SRC kinase inhibitors. The SRC kinase target, downstream of the vascular endothelial growth factor pathway, may enable a way of potentially downregulating both edema and angiogenesis through the same kinase target.
“We specialize in low-throughput, high-batting-average drug development,” Dr. Ulrich said. “Our goal is to make a drug that interacts with a physiological process in the absence of toxicity.” Compounds also undergo early in vivo testing with the Miles assay, a simple intradermal colormetric test on rodents.
One candidate, a TI3 kinase inhibitor, is currently in a Phase II trial of about 50 patients for suppressing pulmonary edema. “Had TargeGen been doing target-based high-throughput screens, we would never have found our first drug currently in Phase II,” Dr. Ulrich noted. “It is not a SRC inhibitor at all; it is an isotype-specific TI3 kinase inhibitor.”
Another promising candidate, TG100801, is being developed as a topically applied kinase inhibitor for treatment of macrodegeneration. Current treatments for wet AMD require invasive injections into the eye. According the Dr. Ulrich, this compound inhibits a complementary set of kinases involved in edema, angiogenesis, and inflammation simultaneously. Phase I clinical trials with TG100801 are expected to start this month.
Small molecule chemistry can create a wide berth of structures for pharma developers. However, de novo synthesis can be time-consuming and laborious. Ming-Qiang Zhang, Ph.D., vp of research at Biotica (www.biotica.com combines chemistry with genetic engineering to expedite the development of compounds.
Biotica focuses on polyketide-based drugs, especially rapamycin, a kinase inhibitor that has been developed for cardiovascular, anticancer, and immunosuppressant applications. Most of the chemical modifications of rapamycin (C51H79NO13) come from a single R site.
The modular architecture of the rapamycin operon allows researchers to alter components of the rapamycin molecule, such as the R group and the molecule’s backbone, by feeding genetically engineered bacteria with starter molecules.
One engineered candidate, Compound A, with an alcohol at the R group and a methyl replaced by a hydrogen on the backbone, is orders of magnitude more potent than rapamycin in inhibiting several in vitro mammary and renal tumors.
One limitation of rapamycin is metabolic instability, a major metabolic site that becomes demethylated by Cyp3A4. By engineering its deletion, researchers at Biotica developed a compound called BC210 that has surprising new properties.
Not only is BC210 more stable than rapamycin, but it also more effectively crossed the blood brain barrier, which potentially opens rapamycin up to treating brain diseases, according to the company. In an orthotopic U87 glioblastoma multiforme model, an aggressive and fatal form of brain cancer, all control mice died by day 37, while the BC210 treated group survived until day 57.
Another surprising lesson is that instead of generating heavier, less effective small molecules, Biotica’s genetic engineering approach has lead to the development of smaller, more effective compounds. “With our technology,” Dr. Zhang said, “we can either manipulate the potency or improve the pharmacokinetics by reducing the molecule weight and not reducing the ligand-binding efficiency.”