Small molecule inhibitors (SMIs) are well-established therapeutics in the pharmaceutical industry. Some, such as Tamoxifen, an inhibitor of estrogen receptor function that is widely used in breast cancer, and flutamide, a prostate cancer therapeutic that inhibits androgen receptor signaling, are among the most successful drugs on the market. While previous SMI drug discovery approaches relied primarily on trial and error testing of chemicals, this has been supplanted by recent advances in genomics and proteomics, combinatorial chemistry, and high-throughput screening that have rapidly accelerated the rate at which compounds are entering the drug pipeline. SMIs can be designed to disrupt key eukaryotic cellular processes, such as kinase signaling pathways and cell division, that have applications in cancer and inflammatory disorders. They can also be developed to specifically interfere with viral and prokaryotic biology in the treatment of infectious diseases.
Cambridge Healthtech’s recent “Drug Discovery Chemistry” conference in San Diego brought together researchers from both industry and academia to highlight recent progress in the field. A recurring theme in these talks was targeting protein-protein interactions in small molecule drug discovery.
Protein-protein interactions are fundamental to myriad cellular processes and, by extension, are essential to the progression of many diseases. Interactions between proteins can be inferred from genomics screens for functional relationships or directly from large-scale proteomics screens.
“In many cases, the biology can tell us what protein-protein interactions might be key targets for therapy,” said Michelle Arkin, associate adjunct professor of pharmaceutical chemistry at University of California, San Francisco and associate director of UCSF’s Small Molecule Discovery Center.
“Some of the best targets are extracellular hormone/receptor interactions that initiate intracellular signaling events, and enzymes that act as functional units within protein complex networks,” she added.
Histone deacetylases (HDACs), for example, have emerged as some of the most popular therapeutic targets in recent years. HDACs catalyze the removal of acetyl groups from nucleosomal histones, to convert chromatin to a “closed” state, resulting in the repression, or silencing, of genes. Targeting the interactions between complexes containing these molecules and specific transcription factors can therefore alter the transcriptional function of a target disease cell and compromise its viability.
Karus Therapeutics is developing a series of selective inhibitors of HDAC6 that were the focus of a talk by its CSO Stephen Shuttleworth.
HDAC inhibitors have shown promise in the treatment of rheumatoid arthritis and other inflammatory disorders. Inhibition of HDAC6, for example, leads to increased expression of the transcription factor forkhead box P3, an important regulator of T-cell function in the immune system, and whose deficiency has been linked to autoimmune disorders such as systemic lupus erythematosus.
“Discovery and development of HDAC6 inhibitors has historically been extremely challenging, and there is currently a dearth of their isoform-specific inhibitors,” said Shuttleworth. HDAC6 has also been implicated in the etiology of neurodegenerative disorders such as Alzheimer disease.
Carl Baldick, a senior investigator in infectious disease research and development at Bristol-Myers Squibb (BMS), turned the focus to the inhibition of the hepatitis C virus (HCV). “There are several key challenges in achieving high cure rates in HCV therapeutics,” reported his colleague Douglas Manion, svp of development, neuroscience, virology at BMS.
“These include avoiding the use of interferon-alpha, shortening the duration of therapy and improved safety and tolerability,” Manion added. An additional obstacle is the diversity of viral genotype as well as geography and treatment experience of patient populations. Assembly of the virion involves interaction of the capsid protein with the NS5A regulatory protein. BMS’ daclatasvir, currently in Phase III, inhibits the function of NS5A and has potent antiviral activity across multiple HCV genotypes.
Other HCV therapeutics in BMS’ portfolio include inhibitors of the NS5B polymerase (INX-189 and BMS-791325) and the viral NS3 protease inhibitor asunaprevir. “We are continuing to explore other ways of attacking HCV, including the potential for entry inhibitors that could be combined with and complement other direct-acting antivirals targeting HCV replication,” said Baldick.
BMS has developed a preclinical assay that allows the evaluation of the potency of entry inhibitors against all HCV genotypes. “The assay uses a panel of HCV pseudoparticles containing functional viral envelope proteins derived from 40 different samples from patients infected with HCV genotypes, 1–5,” explained Baldick.
According to Manion, future prospects for HCV SMI development at BMS include an external collaboration with Janssen Pharmaceutica to evaluate combination therapy of aclatasvir and BMS-986094 with the TMC-435 protease inhibitor, and the development of triazine entry inhibitors. “Current triazine entry inhibitors lack sufficient potency against genotypes 2–5, although it is possible that further chemical modifications to this chemotype could meet this goal. In that case, HCV entry inhibitors could be a promising component of combination therapy,” Baldick noted.