Exploiting Macrocycle Space for Drug Discovery

In the never-ending search for new pharmaceutical agents, significant attention has been focused on the advances enabled by the “omics” technologies, such as genomics, proteomics and metabolomics. These innovations have led to the identification and characterization of an increasing number of promising pathways and targets for therapeutic intervention.

Associated with this resurgence of novel targets, a dramatic shift in drug discovery approaches to biomolecular entities has contributed to a greater number of antibody and protein drug products appearing and advancing in the pipelines of pharmaceutical and biotech companies. Unfortunately, the chemical strategies employed to attempt to modulate these pathways and targets have not experienced a similar transformation. Indeed, many of the targets being investigated are proving intractable to the traditional small molecule structures that dominate historical corporate compound collections.

To address this dilemma, one area that has attracted considerable interest over the last few years is that of macrocycles.1,2Macrocycles are chemical structures containing one or more rings of at least 12 atoms and, as such, are typically larger than the 500 Da molecular weight limit imposed to traditional small molecules by the well-known Lipinski “rules of five.” Importantly, this compound class effectively fills the gap between conventional small molecules and biomolecules (Figure 1), and can offer attractive features of each, the high potency and selectivity of biomolecules combined with favorable pharmacokinetic properties, including oral bioavailability, as well as the ease and lower cost of development of small molecules. Further, a wide assortment of natural products are macrocyclic in nature and have already proven to be a fruitful source of interesting bioactivity with a number of marketed drugs arising from this class.

Detrimentally, preparation of analogues of natural products to modulate the properties or circumvent unfavorable aspects of the initial compounds is usually not possible due to their limited quantity, significant complexity, and poor synthetic accessibility. Nonetheless, macrocyclic compounds represent a potential wellspring for novel pharmacological activity and offer a number of attractive features:
•    Dense, complex functionality
•    Conformational rigidity
•    Structural preorganization
•    Display of diverse interacting groups in extended regions of three-dimensional space
•    Viable approach to protein-protein interaction (PPI) modulators and other difficult targets
•    Underexplored intellectual property space

Figure 1

To date, however, difficulties in the de novo synthesis of macrocyclic structures, particularly in the library format required for the high throughput screening (HTS) campaigns that are a common starting point for most modern drug discovery efforts, have hampered their exploration.

Recently, this situation has changed and an array of innovative technologies have been developed that provide access to macrocyclic compounds of varying size and composition.3 These approaches range from purely chemical in nature to hybrid strategies that combine biological methods such as phage or mRNA display and directed translation systems with one or more chemical steps.4,5 The latter in particular can generate very large numbers of compounds, but tend to also be in the higher MW range, bringing concerns regarding their ability to possess drug-like properties. In contrast, pure chemical strategies often provide structures on the lower MW side of the macrocycle continuum with their concomitant higher potential for favorable physicochemical and pharmacokinetic profiles.

Intending to exploit the advantages provided by this region of macrocycle space, a research collaboration between Cyclenium Pharma, a Quebec-based pharmaceutical company specializing in the discovery and development of novel drug candidates based on proprietary macrocyclic chemistry, and the Institute for Research in Immunology and Cancer — Commercialization of Research (IRICoR) along with Université de Montréal and its Institute for Research in Immunology and Cancer (IRIC) was announced in January. This collaboration will utilize Cyclenium’s proprietary QUEST Library™ of next generation macrocyclic molecules and associated hit-to-clinical candidate optimization expertise in concert with IRIC’s state-of the-art capabilities in biological target identification, characterization and screening, as well as medicinal chemistry. The objective of the collaborators is to discover and develop new pharmaceutical agents for the treatment of cancer and immunological disorders.

“As a chemistry-focused company, it is critical for Cyclenium to find appropriate partners, such as IRICoR, with complementary biological and pharmacological expertise, to provide a robust engine for generating new pharmaceutical agents,” commented Dr. Helmut Thomas, President & CEO of Cyclenium Pharma. “The combination of our unique CMRT™ Technology, together with the significant biology, pharmacology and medicinal chemistry expertise of IRIC provides strong synergy for the development of novel therapeutics against cutting-edge targets in oncology and immunology.” In a similar vein, Cyclenium established a collaboration with Southern Research Institute (Birmingham, Alabama, USA) in April 2014 and has indicated that additional such partnerships in their therapeutic focus areas of oncology, infectious diseases and inflammation/pain will be announced in early 2015.

Figure 2

Although Cyclenium is a relatively young organization, its founders originate from one of the pioneers in the macrocycle field, Tranzyme Pharma, which shuttered its Sherbrooke R&D facility in November 2013 following the merger of its parent company with Ocera Therapeutics. The Cyclenium team has capitalized on its over 15 years’ experience with and significant knowledge base regarding macrocyclic drug discovery in creating its proprietary CMRT (pronounced “smart”) Technology that addresses the deficiencies of the initial efforts in this area, which often fail to deliver compounds with properties appropriate for further development as pharmaceuticals. Indeed, the focus for Cyclenium on the lower end of macrocycle space (MW < 800) is due to the better pharmacokinetic and physicochemical profiles that can be attained with such structures. More specifically, CMRT macrocycles combine variable linker components with bifunctional building blocks, many derived from amino acids, to permit simultaneous investigation of a diverse chemical and topological space (Figure 2). The QUEST Library contains a representative sampling of the compounds occupying this space and enables a rapid survey of it for novel bioactivity. Once initial hits are attained, the modular construction of Cyclenium’s macrocycles simplifies and accelerates hit-to-lead-to-clinic optimization through systematic variation of the linker and building block components.

“With CMRT, we have maintained certain key characteristics from earlier work, but took advantage of the lessons we learned through a myriad of internal and collaborative drug discovery projects to incorporate a number of new aspects that overcome the limitations of the first generation macrocycle technologies,” explained Dr. Thomas. “As such, our strategy combines the best from the past with several novel fundamental design concepts to make CMRT a powerful and versatile approach with definite advantages for macrocyclic drug discovery.” Previous research from the Cyclenium team, while at Tranzyme, was highly successful resulting in the first two synthetic small molecule macrocycles to progress into late stage clinical trials: ulimorelin, an intravenous ghrelin agonist for postoperative gastrointestinal (GI) recovery, which completed Phase III investigation, and TZP-102, an oral ghrelin agonist for GI motility disorders such as diabetic gastroparesis, which reached the end of Phase IIb.

For IRICoR, this latest collaboration is an extension of its interest in the growing macrocycle area, as it is already involved in a partnership, funded by Merck Canada, with Encycle Therapeutics, a biotechnology start-up founded by Dr. Andrei Yudin of the University of Toronto and MaRS Innovation, to develop an orally-bioavailable macrocycle drug to target integrin α4β7, which is involved in the inflammatory process in a number of diseases, most notably for inflammatory bowel disease.

“Collaborating with Cyclenium is a natural fit for our business model,” according to Steven J. Klein, Ph.D., Vice-President, Business Development at IRICoR. “We had a previous successful collaboration with Helmut and his team while they were at Tranzyme. We plan to initiate our new research effort together by including the Cyclenium QUEST Library™ in a number of upcoming HTS campaigns for novel targets in oncology and immunology, and in particular for PPI-based screens.”

Figure 3a

IRICoR’s main objective is to rapidly translate highly innovative scientific projects from IRIC, UdeM and various centres into high value novel therapies in oncology, immunology and related indications through strong partnerships with the private sector, thereby efficiently bridging the innovation translation gap between early stage academic research and industry (Figure 3).

Figure 3b

IRICoR is a fully-integrated drug discovery and commercialization centre, with one of the largest industry-experienced academia-based medicinal chemistry groups in Canada. In addition to the collaborations with Cyclenium and Encycle Therapeutics, IRICoR has numerous active drug discovery partnerships with a number of companies, including Bristol-Myers Squibb, Merck, Pfizer, Pharmascience, and Domain Therapeutics. “In addition, we have several ongoing drug discovery and development projects with the Centre for Drug Research and Development, MaRS Innovation, and Amorchem,” continued Dr. Klein. “We look forward to a long and productive collaboration with Cyclenium.”

Given the exciting potential and largely unexplored nature of the macrocycle space, it can be expected that additional collaborative efforts to take advantage of the particular expertise of organizations with an established presence in this research area, like Cyclenium and IRICoR, will continue to appear over the next couple of years.

1.    Diggers, E.M.; Hale, S.P.; Lee, J.; Terrett, N.K. Nat. Rev. Drug Disc. 2008, 7, 608-624.
2.    Marsault, E.; Peterson, M.L. J. Med. Chem. 2011, 54, 1961-2004.
3.    Terrett, N.K. Drug Disc. Today Tech. 2010, 7, e97-e104.
4.    Bionda, N.; Cryan, A.L.; Fasan, R. ACS Chem. Biol. 2014, 9, 2008-2013.
5.    Bashiruddin, N.K.; Suga, H. Curr. Opin. Chem. Biol. 2015, 24, 131–138.

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