Synthetic Protocol Published for Promising Anticancer Compound
Tyler Davis and Jeffrey Johnston, from Vanderbilt University in Tennessee (USA), have designed a straightforward synthetic route for the promising anticancer compound Nutlin-3. No full protocol for the synthesis of the compound had previously been published. Now, Johnston and Davis describe a highly selective synthesis for creating the correct enantiomer of the compound.
Discovered in 2004 by researchers at Hoffman–Roche, nutlins are a group of compounds that feature a nitrogen-containing heterocycle. Early studies into the compound class revealed it was an inhibitor of the key protein–protein interaction between MDM2 and p53, implicating their potential use in the treatment of cancer. Nutlin-1 and Nutlin-2 were also identified as potential anticancer compounds in the Hoffman–Roche study with Nutlin-3 the more effective. The MDM2–p53 interaction that the compounds inhibit induces a growth-inhibiting state in cancer cells called senescence. Papers on the efficacy of such compounds continued to be published in the intermittent years but none described a synthetic route.
Nutlin-3 contains multiple chiral centers and, therefore, synthesizing the correct enantiomer of the compound is difficult. Johnston and Davis’s full synthetic route, highlights the aza-Henry or nitro-Mannich step as the most important (see Figure). In this step a nitroalkane is added to an imine in the presence of an electron-rich chiral bis(amidine) catalyst. The Vanderbilt researchers screened many different catalysts but the one chosen had up to a 93% enantiomeric excess over 13 examples. The chosen catalyst’s success is owing to its chirality ensuring only one face of the molecule is able to react and its geometrical constraints result in one enantiomer being synthesized over the others. The exact mechanism is not known currently, although the researchers hypothosize that the nitroalkane forms a salt with the catalyst by donating a proton.
The Vanderbilt duo hope that a similar synthetic route can be used to obtain derivatives of Nutlin-3 and that the synthesis devised will aid investigations on the compound’s anticancer activity.
Source: Davis TA, Johnston JN. Catalytic, enantioselective synthesis of stilbene cis-diamines: a concise preparation of (-)-Nutlin-3, a potent p53/MDM2 inhibitor. Chem. Sci. DOI: 10.1039/c1sc00061f (2011) (Epub ahead of print).
Industry–Academic Partnership Makes Cancer Discovery
Targeting tumor blood vessels is not a novel strategy for anticancer drug-design studies, but a collaboration between researchers from Queen’s University Belfast (UK) and Almac Discovery Ltd has revealed a new blood vessel pathway that could be targeted. The treatment could be used for cancers that are resistant, or do not respond, to current treatments.
Therapeutics that target blood vessels, such as Sorafenib (Nexavar), Sunitinib (Sutent) and Bevacizumab (Avastin), have been approved by the US FDA and have various targets such as the vascular endothelial growth factor (VEGF) and certain kinases. The researchers in this study did not look to target a specific protein or gene but instead studied the natural antiangiogenic potential of the FK506-binding protein like (FKBPL). Using this protein as a model, the team developed small peptide-based molecules that were highly effective in prostate and breast cancer models.
The molecule will continue to be investigated by Almac Discovery and Queens University Belfast and hope that it will eventually lead to a successful drug that targets tumor angiogenesis by this new pathway.
Source: Valentine A, O‘Rourke M, Yakkundi A et al. FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism. Clin. Cancer Res. 17, 1044–1056 (2011).
Phrma Wait for US FDA Guidelines on Social Media Usage
The US FDA has postponed the publication of its draft guidance on the use of social media following the claim by the Pharmaceutical Research and Manufacturers of America (PhRMA) that social media could have ‘incredible health benefits’.
Many PhRMA member companies expressed a desire to use social media in order to interact with patients in the same way that the FDA and the White House currently use Facebook, Twitter and other social networking sites. PhRMA’s plans include the use if a universal symbol that would guide the patient to a website with FDA-approved information on the risk and benefit of certain drugs.
The guidance was originally due to be released in December 2010 but it was not published. As a result, the FDA claimed it would aim to deliver guidance on one of five topics in early 2011. These topics included the use of social media for online communications for which manufacturers, packers or distributors are accountable and the use of links on the internet and correcting misinformation.
The FDA has stated that it is developing multiple draft documents on a number of the issues but says that it cannot provide a definitive timeframe for the release of the document due to the extensive work and review process. The guidance has also been delayed as the FDA did not want documents to become quickly outdated as technology advances.
Assistant General Counsel Jeffrey Francer spoke of his frustration in a PhRMA press release stating that, “As PhRMA eagerly awaits the FDA’s guidance on this important issue, we note that FDA itself is making almost daily use of Twitter, Facebook and other social media. Clearly, social media can be used to discuss new medical advances in appropriate ways that benefit patients and healthcare professionals, and improve the public health.”
Source: PhRMA Statement Regarding FDA Oversight of Promotion Online: www.phrma.org/media/releases/phrma-statement-regarding-fda-oversight-promotion-online
Cancer Drugs Fund to Provide £200 Million-A-Year
The UK government’s Department of Health has established the £200 million-a-year Cancer Drugs Fund. The aim of the fund is to create more funding for rare cancers and to allow patients access to drugs recommended to them by their physicians that are not on the National Institute for Clinical Excellence (NICE) accepted list.
The fund will run from March 2011 until 2013 but the UK government had already made £50 million available from October 2010. Drugs deemed as cost and clinically effective by NICE will continue to be supported by the NHS but the fund will now allow patients access to drugs that their physicians feel are required but, which are not necessarily considered cost-effective by NICE.
The Health Secretary, Andrew Lansley stated in a Department of Health press release that, “The interim fund has already helped over 2000 cancer patients across England. We are confident that the £600 million Cancer Drugs Fund will, over the next 3 years, continue to meet this previously unmet need and improve the lives of many thousands more cancer sufferers, giving them precious extra time with their loved ones.”
Source: Delivering on NHS modernisation: Government launches £200 million a year Cancer Drugs Fund, as raft of improvements is rolled out in the new financial year: www.dh.gov.uk/en/MediaCentre/Pressreleases/DH_125725
Potential Treatment for Heterotopic Ossification Discovered
Researchers from Thomas Jefferson University (USA) have performed a study that identifies a possible treatment for heteropatic ossification (HO), a debilitating and painful buildup of bone tissue. The disease appears in two main forms: a congenital disorder mostly affecting children and a type triggered by severe injuries and wounds found in surgical patients and wounded military personnel.
The congenital form of HO is called fibrodysplasia ossificans progressiva and is usually identified by the time the child is 5- or 6-years old. The condition affects approximately 700 children in the USA but is progressive and cannot be treated with surgery as this would trigger explosive HO, seriously risking the child’s life. The mechanism for the other type of HO is not fully understood but it is believed that trauma, deep burns and surgery can cause inflammation that is then followed by the arrival of skeletal cells that first develop into cartilage cells and are then substituted for bone tissue.
In the study, led by Masahiro Iwamoto and Maurizio Pacifi (both now at The Children’s Hospital of Pennsylvania [USA]), the researchers used mouse models of HO to study the effect of nuclear retinoic acid receptor-γ (RAR-γ) agonists. The RAR-γ agonist compounds target the regulatory pathway that forms the cartilage in the first step of HO. The results of the study showed that the RAR-γ agonists did prevent HO from occurring in the mice in complete contrast to the control set of mice, which developed the bone masses. There were minimal side effects and the protective effect of the RAR-γ agonists continued even after the mice were no longer being given the compound.
In a second test the group studied the effect that the RAR-γ agonists had on mice that had been genetically altered to express mutant proteins as in fibrodysplasia ossificans progressiva. Once more the compounds proved to be successful, blocking the progression of HO.
Masahiro and Pacifi and their coworkers have urged caution over the success of this study stating that more preclinical investigations must be carried out before the RAR-γ agonists enter human clinical trials for HO. The group does note, however, that a RAR-γ agonist has entered human clinical trials for another disease and hope that this could aid the process should the compounds ever enter clinical trials.
Source: Shimono K, Tung W, Macolino C et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nature Medicine DOI: 10.1038/nm.2334 (2011) (Epub ahead of print).
Possible Target for Therapy-Resistant Breast Cancer Identified
A research team from the Georgetown Lombardi Comprehensive Cancer Center (USA) has found a potential biological target for breast cancers that have become resistant to antiestrogen therapies. Resistance to the currently used drugs, such as Tamoxifen and Faslodex, is not fully understood but now Ayesha Shajahan and coworkers have unveiled a possible pathway to target in the development of future drugs.
The group discovered that breast cancer cells guard themselves from antiestrogen drugs by switching on a biological process known as unfolded protein response (UPR), which is normally activated when proteins are produced that do not have the correct shape. When UPR is triggered, two responses are observed. One response is to protect the cells and the other turns on a pathway that destroys the cell and in anti-estrogen therapy-resistant breast cancer UPR activates the protection pathway, hence drugs do not enter the cell. The group analyzed the proteins expressed when UPR is activated in order to find a potential target for this type of breast cancer. XBP1 subtype is overexpressed when the UPR is triggered and the group hopes to target this protein in its future investigations to find active compounds to switch off the UPR response.
The team presented its findings at the American Association for Cancer Research’s 102nd Annual Meeting in April 2011.
Source: Shajahan AN, Hickman FE, Cook K, Clarke R. XBP-1 promotes cell survival by activating the unfolded protein response (UPR) in antiestrogen resistance in breast cancer. Presented at: American Association for Cancer Research 102nd Annual Meeting Orlando, FL, USA 2–6 April 2011.