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Preparation of Novel Tyrosine Kinhase Inhibitors

Despite educational efforts against sun exposure, the incidence of melanoma, the most aggressive form of skin cancer, is increasing. The yearly worldwide incidence of melanoma was estimated at 211 000 cases with 65 000 deaths.  In 2013, the incidence is close to 350,000 cases. In Kazakhstan, 30 299 persons were diagnosed with malignant tumors in 2011. Furthermore, an average of 17 000 deaths due to cancer is recorded annually, making it the second cause of mortality in the country. Skin cancer represents 10.7% of these malignancies with only a 57% survival rate. For comparison, the European and American survival rates for melanoma are 86% and 92%, respectively. 

Therefore, there is an urgent need to develop new and affordable therapies in Kazakhstan.  Although early stage melanomas are efficiently treated by surgery; treatments for late stages or recurrent disease show limited efficiency and very often require very expensive targeted therapy.  Moreover, metastatic melanoma is usually resistant to standard chemotherapies. The recent discovery that 50% of melanoma carry a BRAF mutation, usually in position V600E located in the kinase domain, has led to the development of BRAF tyrosine kinase inhibitors such as vemurafenib and dabrafenib. Another therapeutic approach involves immune system modulation by monoclonal antibodies such as ipilimumab, which offers about 15% long-term remission.  

Vemurafenib only effects melanoma cells displaying the V600E BRAF mutation and, moreover, promotes the growth of cells lacking BRAF mutations.  Only half of melanoma patients are candidates for this targeted agent, which offers a median progression-free survival of about 8 months. Although vemurafenib elicits a clinical response in 50 - 70% of patients, it causes significant side effects, including arthralgia, photosensitivity, skin rash, and promotes the transformation of actinic keratosis into skin cancers.  Long-term survival remains elusive for most patients.

Because very few patients with metastatic cancers can be cured, the scientific community must develop more efficient anticancer therapies.  Herein, we propose, in collaboration with Dr. Claire Verschraegem from the University of Vermont Cancer Center, one strategy in which small molecule inhibitors are modified to increase their specificity and decrease toxicity. 


Taking advantage of the presence of the metal in the drug, we developed an electrochemical method to modify the ligand beared by the metal.


As expected, our first generation of drugs showed greated anti cancer activity then the organic ligand alone.