Furthermore, ALK gene amplification and mutation were also reported in glioblastma. For example, the most frequently observed form is EML4-ALK in non-small cell lung cancer and the most frequently found form is NPM-ALK in ALCL. Different ALK fusion forms were found for different diseases. ALK gene amplification and activating mutants were also reported in glioblastoma (Chen et al., 2008 George et al., 2008 Janoueix-Lerosey et al., 2008 Mosse et al., 2008). In addition, ALK gene fusions not only play important role in non-small cell lung cancer, they are also found be critical in for many other diseases such as inincluding patients with ALCL patients, colorectal cancer (Lin et al., 2009 Lipson et al., 2012), IMT (Lawrence et al., 2000) ovarian cancer (Ren et al., 2012) diseases. These different forms of ALK fusion proteins are also highly depend on ALK kinase activity and sensitive to ALK kinase inhibitors. There are more than 20 different genes were reported serve as partners of ALK. Treating ALK fusion positive patients with specific tyrosing kinase inhibitors provides great benefit to patients in clinics and it made a new milestone in lung cancer therapy. And the objective response rate was increased from 20% to 65% comparing those treated with chemotherapy.
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It increased median progression free survival from 7.2 months with chemotherapy to 9.6 months, and which was increased to 13.6 months in Asian patients (Nishio et al., 2017). Regardless of with or without pretreatment, Crizotinib showed greater benefit to patients. With this drug, the progression free survival of the patients was increased to about 10 months (Nishio et al, 2017). In 2016, Crizotinib was approved to treat non-small cell lung cancer patients with ROS1 (c-ros oncogene 1 receptor tyrosine kinase,c-ros) mutation. In 2011, Crizotinib developed by Pfizer was approved by FDA to treat ALK positive non-small cell lung cancer. Several ALK kinase inhibitors have been approved to treat ALKmutant positive cancer. Such ALK fusion positive cancer cells are highly dependent on ALK kinase activities and inhibition of ALK kinase activity leads to death of these cells. ALK can form fusion proteins with many other different partners, such as KIF5B, to drive cancer formation (Takeuchi et al. In lung cancer, the major fusion partner with ALK is Echinoderm microtubule-associated protein-like 4, EML4.
ALK forms fusion genes with different partners and leads to consitutively activated ALK kinase activities to transform normal cells become cancer cells (Soda et al., 2007 Choi et al., 2008 Cha et al., 2016).
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Gene fusion of this gene is a strong cancer driver gene which was firstly discovered in anaplastic large cell lymphoma patients, and later were found in many other diseases including diffused large B-cell lymphoma and Inflammatory Myofibroblastic Tumor (IMT) (Wellmann et al., 1997). In clinics, such mutations are often observed in young non-smoker patients (Soda et al.
The incidence ratio has no significant difference in Asian and western caucasion populations. In lung cancer, patients with EML4-ALK gene fusion are about 3-7% of the total number of non-small cell lung cancer patients. Treating ALK (Anaplastic Lymphoma Kinase) mutation positive non-small cell lung cancer with specific small molecular tyrosine kinsae inhibitors greatly improved the efficacy of cancer therapy and patient quality of life. Recently precision medicine provides targeted therapy to patients with specific driver genes which greatly reduced the toxic effect or traditional chemotherapy and radio-therapy and greatly improved patients quality of life. This is because traditional chemotherapy and radio-therapy killed normal cells together with cancer cells, which causes decreased immunity and dysfunction of patients physiology. And this rate have doesn't change too much since 70s in the last century.
The five-year survival rate of lung cancer is also very low, and it is only about 17%. In China, the incidence of lung cancer is already surpassed other types of cancer, and each year there are about 800,000 people died from lung cancer. Lung cancer is the leading cause of cancer related death in China and the world wide. The present disclosure relates generally to compounds of formula (I) for cancer prevention and therapy, and their use in anti-cancer therapy, especially against cancer-related proteins including ALK, MET, ROS1, EGFR and FLT3.
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