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Abou-Gharbia: Discovery of innovative small-molecule therapeutics

Small molecules, including natural products, have dramatically expanded the impact of basic biomedical research, creating opportunities for remarkable discoveries and the identification of novel therapeutics. They are invaluable tools that facilitate the study of biological processes and validation of disease targets. Breakthrough discoveries produced through the examination of biologically active small molecules include innovative treatment of cancer, immune-mediated inflammatory diseases, neuropsychiatric disorders, neurodegenerative conditions and many others. This presentation will highlight three programmes that led to the discovery of first-in-class therapeutics. These key drugs alleviate the suffering of millions of patients around the globe.

Effexor® and Pristiq® – new approaches for the treatment of depression

The discovery of the serotonin–norepinephrine reuptake inhibitors (SNRIs) venlafaxine (Effexor®, Pfizer, Surrey, UK) and desvenlafaxine (Pristiq®, Pfizer, Surrey, UK) (Figure 1) fundamentally changed the treatment paradigm for patients suffering from depression. This class of compounds provides patients with faster onset of action than earlier antidepressants and demonstrates efficacy in refractory patients who do not respond to tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). To date, more than 25 million patients worldwide have benefited from the discovery of Effexor and Pristiq.


Effexor® and Pristiq®.


Torisel® and ILS-920 – novel semi-synthetic immunophilin mTOR inhibitors for the treatment of renal cell carcinoma and stroke

The mammalian target of rapamycin (mTOR) pathway has proven to be an important drug target in several disease areas, leading to significant scientific exploration. It has been demonstrated that this pathway plays a key role in the progression of renal cell carcinoma. Renal cell carcinoma is the most common malignancy of the kidney and accounts for 2–3% of all adult cancers. Prognosis of advanced renal cell carcinoma is very poor with a 5-year survival rate of 5–10%. Globally, there are over 209 000 new cases annually and 102 000 deaths associated with renal cell carcinoma. The novel immunophilin mTOR inhibitor temsirolimus (Torisel®, Pfizer, Surrey, UK) (Figure 2) demonstrated a significant increase in median overall survival compared with those receiving interferon-α, the standard drug for care, and was hailed as a major breakthrough in the treatment of renal cell carcinoma following its approval in 2006.


Torisel® and ILS-920.


Separately, mTOR inhibitors could potentially have a positive impact on the lives of stroke patients. The impact of stroke is astounding. Worldwide, stroke accounts for over 4 million of the 50.5 million deaths each year. There are an estimated 7 000 000 stroke survivors in the USA alone, with nearly 800 000 new strokes occurring annually. The direct and indirect costs of stroke in 2010 were over $73 billion. Apart from the thrombolytic agent tissue plasminogen activator alteplase (Actilyse®, Genentech, Inc., South San Francisco, CA, USA), there is no effective treatment for stroke. Clinical use of Actilyse® is extremely limited to specific types of stroke and the time between infarct and initiation of treatment is critically important. Over 1000 neuroprotective drug candidates have failed in clinical trials. These observations suggest that neuroprotection alone is not sufficient for stroke therapy. Neuroregeneration is also necessary. ILS-920 (see Figure 2), a novel immunophilin mTOR inhibitor, not only displays neuroprotective activity but also promotes functional recovery, a clinical strategy heralded by many to be the way forward for stroke therapy. The importance of the discovery of immunophilin mTOR inhibitors has been recognized by the issuance of over 100 US patents.

Mylotarg™ – the first approved conjugate antibody anticancer drug for the treatment of acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a blood cancer characterized by rapid growth of abnormal white blood cells. These cells accumulate in the bone marrow and interfere with the production of normal blood cells. Although AML is a relatively rare disease, it is the most common form of acute leukaemia and incidence rates are predicted to increase as the population ages. Treatment options for patients were expanded in 2000 with the launch of the antibody drug conjugate gemtuzumab ozogamicin (Mylotarg™, Pfizer, Surrey, UK) (Figure 3). This drug was the result of the discovery of multifunctional linkers useful for attaching the potent cytotoxin calechiamicin to external lysine residues of antibodies. Linking this compound to antibodies specific to cancer cell surface protein CD33 produces antibodies that could specifically target cancer cells, facilitating the delivery of anticancer agents to their intended target.


MylotargTM – the first approved conjugate antibody anticancer drug for the treatment of AML.


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