November 1, 2006 (Vol. 26, No. 19)

Avoiding Roadblocks in Development

Small molecules are experiencing renewed interest in drug development, exemplified by the “Biotech for Small Molecule Therapeutics” section during “BioFine USA” held recently. Presenters shared their business and biological strategies, which included focusing on a smaller number of drug-like molecules and testing candidates immediately in biological models.

Zhu Shen, Ph.D., head of business development at Immusol (, presented the company’s approach to transforming known compounds into treatments for diseases typically not associated with small molecules.

“There is not a big demand for novel targets these days,” Dr. Shen said. “Most companies large and small focus on getting compounds in later and later stages of clinical development.” Immusol focuses on getting small molecule drug candidates from preclinical to clinical stages for disease targets such as hepatitis C virus (HCV) and wet age-related macular degeneration (wet AMD).

In HCV drug development, many companies focus on RNA polymerase inhibitors or protease inhibitors that follow the success of HIV drug development and commercialization or interferon-based immune system boosts. Researchers at Immusol, however, screened compounds with known functions, a way to get from candidate to approved drug faster, it claims.

“Through screening, we discovered that certain compounds have unexpected effects for other diseases that we are studying, like HCV,” Dr. Shen said. These old molecules are then structurally changed to improve potency and desirable drug-like characteristics.

With this approach, Immusol has so far generated four HCV lead compounds, with an IND filing planned for 2007. Currently, lead compounds are undergoing tests in pseudo-particle in vitro assays based on HIV entrance assays.

Researchers at Immusol identified an anticancer compound with anti-inflammatory and antifibrotic scarring properties, both symptoms of wet AMD. Preclinical testing with a laser-induced rat CNV model is currently under way.

New Paradigm for Development

Peter Ulrich, Ph.D., is cofounder and CEO of TargeGen (, 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 ( 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.”

Targeting Pathways

Rather than focusing on molecular targets within a cell, Cylene Pharmaceuticals( focuses on novel drug targets within recognized anticancer biological pathways as an inroad to discover new drugs.

“Directing drugs against novel targets readily serves unmet medical needs and can differentiate a company’s identity and create more lucrative market opportunities without the risk of competing drugs acting through similar mechanisms,” said William Rice, Ph.D., the company’s president and CEO.

The company was founded to develop drugs that target quadruplex DNA, a 3-D structure formed by specific sequences of DNA. Cylene identified a particular quadruplex DNA structure required for ribosomal RNA biogenesis, a validated pathway through which many marketed cancer drugs exert their pro-apoptotic action.

By basing its lead candidate, CX-3543, on a fluoroquinolone template, the company says it avoided development risks associated with novel molecules because fluoroquinolones represent a highly successful class of antibiotic drugs that are known to interact with protein-DNA complexes. After removing antibiotic activity, Cylene demonstrated that CX-3543 localizes to the nucleolus of cancer cells, targets the quadruplex DNA motif, inhibits rRNA biogenesis, and inhibits growth of many types of tumors in a xenograft model.

In Phase I, CX-3543 is showing early signs of biological activity, according to Dr. Rice, and Cylene expects to introduce CX-3543 into Phase II trials in the first half of next year.

In the second part of his presentation, Dr. Rice talked about the importance of building a “picket fence of patents” to protect IP. “Every action a company can take to file meaningful provisional and full patents,” Dr. Rice said, “keeps others from chiseling away at your IP space.” So far, Cylene has filed 30 patents around its lead molecule and associated technologies. Two key patents on composition of matter were awarded this year.

Transformation into Drugs

No matter how exciting a small molecule drug candidate may seem during research, eventually the work has to translate to the consumer as a drug product. Jeffery Bibbs, Ph.D., co-founder and CEO of Pharmatek Laboratories (, talked about how labs need to ensure early on that small molecule prospects can be transformed into drugs.

“There are small molecules, and there are small molecules that are druggable,” Dr. Bibbs said. “Sometimes companies will push too hard to make a compound work.” A druggable compound is one that shows good solubility and stability and is manufacturable as an API and as a drug product.

Dr. Bibbs highlighted two case studies that illustrated this push. One company was testing an orally dosed compound on experimental animals. Unbeknownst to the company scientists, the drug degraded into a new compound overnight. “That is the drug that was being injected into the animal model. “They were making their claims on the wrong molecule.”

In another example, an anticancer drug candidate was stable at -70º. “It was a mess. They wanted to make this drug work so badly, they probably spent $2 million on it,” Dr. Bibbs noted. It was destined for failure—“not everyone can store drug in -70º freezers.”

This disconnect comes from inexperience, according to Dr. Bibbs. “Every compound is unique. For each one, scientists need to think about solubility, stability, and manufacturability of both bulk drug, and final drug product, which includes inactive ingredients.” Dr. Bibbs said that his company and others spend significant resources educating people on assessing druggability before declaring a drug candidate.

A little common sense can avoid future headaches in drug development. “Once you file an IND on a compound, you are stuck with that compound,” Bibbs warned. “There is no reason why a company should throw good money after a bad, nondruggable compound.”

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