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Mar 15, 2008 (Vol. 28, No. 6)

Surmounting Small Molecule Challenges

Natural Product-Based Techniques See Resurgence of Interest and Applicability

  • Companies are developing new platforms to enhance their small molecule discovery efforts and, in turn, the molecules themselves. This is due in part to increased pressure to develop new drugs. With an estimated $20 billion of brand-name drugs going off patent this year, the biopharma industry is scrambling to find new sources of revenue.

    At Zing Conferences’ “Small Molecule Drug  Discovery” meeting held in January, presenters addressed a myriad of challenges encountered in working with small molecules.

    “The challenge with kinases,” explained Chris Larson, Ph.D., former associate director of biology at Kemia, “is that they use ATP as a cofactor—they have that interaction that all inhibitors want to block.”

    According to Dr. Larson, Kemia addressed this situation by seeking out an inhibitor that would not directly compete with ATP but would instead alter the confirmation of the enzyme so ATP wouldn’t fit any more. Once his group confirmed the inhibition of p38 kinase activity, compounds like KC706 were developed based on public information regarding enzyme structure and modeling.

    In the past, Dr. Larson said, marketed enzyme inhibitors have not been exquisitely selective, often inhibiting several kinases. It is critical, however, to get more specific against a kinase target of interest to increase safety and reduce side effects. “For cancer applications, safety is not as important as it is for chronic diseases like rheumatoid arthritis where it is key to have high selectivity for the kinase of interest,” he noted.

    KC706 is unique because of its safety in animal models, its once-a-day oral dosing, and its activity against disease models in terms of inhibiting enzyme, Dr. Larson reported. Kemia has completed two Phase II trials with KC706 and is currently in a third trial for autoimmune conditions including rheumatoid arthritis, Crohn’s disease, COPD, and psoriasis.

    Another potential use for this compound is to elevate good cholesterol (HDL), claimed Dr. Larson. “We determined that it was not a p38-mediated effect but an off-target effect.” An efficacy trial in patients with elevated triglycerides showed that they could be safely dosed for six weeks. “KC706 raised HDL levels about 15 to 20 percent. This compound was a great example of serendipity in drug discovery.” 

    Mimicking Nature

    Natural products have historically been central to drug discovery, but interest waned in the 1990s due to the fascination with combinatorial chemistry, explained Jean-Yves Ortholand, Ph.D., CEO at Edelris. “Now there is a rebirth of natural products but in modified ways that include genetic engineering or synthetic production of natural products to produce new entities of interest.”

    Edelris’ strategy is based on the concept of diversity-oriented synthesis developed by Stuart L. Schreiber, Ph.D., an investigator at the Howard Hughes Medical Institute and Morris Loeb Professor of the Department of Chemistry and Chemical Biology at Harvard University. Though diversity-oriented compounds are made synthetically, their complexity mimics that of nature. “This strategy takes into account strong medicinal chemistry dimensions,” Dr. Ortholand noted.

    There are several advantages to this approach, he continued. “Natural products or natural mimics tend to be 3-D and offer chirality, often providing enhanced probability of biological interactions. Some of the properties found in our screening molecules are new or nonexistent in competitor collections.”

    Keymical Collections™, these natural product-like screening collections, now include about 6,000 molecules. Edelris will be releasing additional collections of 1,500 molecules within the next six months. According to Dr. Ortholand, “the compounds are designed to provide options, accessibility, and analogues if hits are found.”

    Using another methodology that originated at Harvard University, researchers at Ensemble Discovery are designing macrocycle compound collections. “David Liu, Ph.D., professor of chemistry and chemical biology, devised a way to use DNA to drive chemical synthesis in a controlled fashion that is analogous to the way nature uses DNA to make proteins,” stated Nick Terrett, Ph.D., CSO. “We have industrialized the method in DNA Programmed Chemistry and made it robust and scalable in order to make thousands of macrocycles called Ensemblins, which contain ensembles of interacting groups.

    “These macrocycles have a molecular weight above 500, enabling them to disrupt protein-protein interactions. In addition, their ring-based structure reduces entropic loss when binding to a protein surface. People have known for many years that macrocycles are special compounds because of their scaffold and confirmational preorganization. There is also good evidence that these compounds can have good pharmokinetics and potentially a good half-life with low toxicity,” added Dr. Terrett.

    Although synthetically challenging to make, Ensemble has developed a method to enhance the process of going from a linear precursor to a cyclic molecule. “We have a process that allows us to purify and isolate only products where cyclization has occurred. We can make tens of thousands of macrocycles simultaneously in the same reaction vessel.”

    DNA is used to drive synthesis of macrocycles and also used as an encoding strand to identify compounds that bind to drug discovery targets. Scientists at the company take a collection of macrocycles with the DNA sequence still attached and are able to determine the structure of compounds that bind to proteins by amplifying the DNA using PCR.

    Pain Compounds

    Currently available opioid analgesics interact with the mu subtype opioid brain and spinal cord receptors. While effective at reducing pain, these therapeutics reportedly have high abuse potential and serious side effects. Adolor’s research platform is based on cloned, human opioid receptors and is designed to develop orally active delta agonists that stimulate the delta opioid receptor. This receptor has potential use in the modulation of pain. It also exhibits a lower side effect profile than traditional mu opioid agonists, according to the company.

    Bertrand Le Bourdonnec, Ph.D., principal research investigator at Adolor, presented data on a prototype delta opioid agonist compound, ADC00013987, for which the company is working to improve binding affinity of the target. “One of the major hurdles we encountered was undesirable activity at a potassium channel that was linked to severe cardiovascular toxicities including arrhythmias. Some drugs have been pulled off the market for this reason.”

    Dr. Le Bourdonnec and his group engineered a structure activity relationship against this off-target ion channel and identified a molecule that is potent in binding to the delta opioid receptor with marginal activity at the potassium channel.

    Another challenge was to develop an orally active model in animal pain models. “We did a lot of pharmacokinetic studies to find appropriate characteristics of the molecule. The resulting compounds have shown robust effects in inflammatory and neuropathic pain in animal models,” stated Dr. Le Bourdonnec.

    Protease Inhibitors

    Although the protease market declined substantially a few years ago, researchers at Ambrilia Biopharma thought there was still a need for proteases due to the emergence of resistant viral strains and therapy failure as a result of the lack of patient compliance. “We had a potent compound, but didn’t like its pharmacokinetics,” explained Brent Stranix, Ph.D., director of chemistry. “We tried to modify the molecule to be more stable, but we kept losing potency. We decided to use a pro-drug approach and were able to make the drug better.”

    PPL-100 binds specifically to HIV-1 protease and has a unique structure, Dr. Stranix said. “We tried to build in flexibility, something that is usually avoided. PPL-100’s flexibility is due to a longer internal spacer than other compounds, which are compact. Additional features include a high genetic barrier, reduced resistance, a long half-life without ritonavir boosting, and oral administration.”

    Ambrilia completed a Phase I single-dose and a repeat-dose pharmacokinetic study, which suggested a favorable safety and tolerability profile.

    All of the aforementioned challenges and many more not mentioned make small molecule discovery seem a bit daunting, yet new small molecules continue to be discovered and developed, which keeps confidence high in the research labs.



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