The development trend of anti-tumor drugs in the future! Which small molecule kinase inhibitors have been approved by the FDA in the past 20 years?

Guide: Only the innovation of science and technology and multidisciplinary joint innovation efforts, in order to faster small molecules to the market!caption:the treatment of cancer, whether in terms of the economic properties of the drug or the affordability of patients, small molecule-targeted drugs have become and will become an important clinical option for patients in the long term (although also expensive...) The purpose of this article is to review dozens of small antitumor molecular kinase inhibitors approved by the FDA over the past 20 years to further understand future drug development trendsthe FDA approved dozens of small molecular kinase inhibitors for tumor treatment
2020, The Lancet published an article summarizing dozens of anti-tumor small molecular kinase inhibitors (see Schedule 1), introducing the listed drugs corresponding to different target-pathwaysAlthough the approved small molecular kinase inhibitors are mostly based on extended survival in patients with advanced cancer patients who are difficult to treat with conventional chemotherapy, these drugs show significant advantages over cytotoxic chemotherapy and have relatively few side effectssmall molecule kinase inhibitors, which can be divided into multi-target kinase inhibitors and high-selective small molecule kinase inhibitors (usually called single-target drugs, but in practice there are very few "single targets")Multi-target kinase inhibitors to develop their anticancer activity by simultaneously targeting a wide range of kinases, which are often based on histological diagnosis and do not require additional personalized patient selectionHigh-selective small molecule kinase inhibitors, which typically have fewer targets and, in some cases, inhibit cell signaling, a single component;Schedule 1:FDA approved anti-tumor small molecular kinase inhibitorsmulti-target kinase inhibitorshigh-selective small molecule kinase inhibitors.1 to multi-target kinase inhibitorstypical examples of sorafenib and shonetinib; Since these drugs may inhibit a variety of kinases, the development of multi-target kinase inhibitors is largely empirical, with some exceptionsexample, Imartinib is the first FDA-approved small molecule kinase drug to target BCR-ABL fusion proteins, which is the disease-causing target of chronic granulocytic leukemia (the indications in I'm not a drug god), and Imartinib is an effective KIT inhibitor and an FDA-approved combination with other multi-target kinase inhibitors to treat gastrointestinal intercomma with KIT mutationsNO.2 to high-selective small molecular kinase inhibitors
some tumors show strong dependence on cancer genes in the clinic, high-selective small molecule kinase inhibitors have the potential for potential antagonistic targets, while minimizing the off-target effects that may lead to dose reduction or unbearable side effectsEGFR inhibitors, such as urlotini and giphatinib, were originally developed without specific patient choice and are effective in non-small cell lung cancer patients treated with standard cytotoxic chemotherapyAfter the discovery of significant benefits in some patients (a significant increase in total survival), EGFR mutations were identified as predictable biomarkers and eventually redefined both drugsThe discovery establishes a new model for deciding which small molecule kinase inhibitors to use based on the presence of biomarkersSuch as the method used in melanoma patients selective mutation BRAF Val600Glukinase inhibitors, resulting in several years of the approval of several drugs (vemurafenib, dabrafenib and encorafenib)Figure 1: Small molecular kinase inhibitors marketed drugs corresponding to targets
molecular screening and evolving clinical trial framework, the first trial was to screen more than 1500 tumor patients from patients with drug-resistant non-small cell lung cancer to recruit 82 ALK gene re-erunding patientsThe problem was that patients with advanced cancer often deteriorated rapidly and could not wait for the results of biomarker tests, and issues such as eligibility for admission created difficulties for the tests; Small molecules such as the NTRK gene corresponding to the small molecule TRK family inhibitors (larotrectinib and entrectinib), as well as the PD-1 inhibitor pembrolizumab, are FDA-approved treatments based on common biomarkers rather than the site of the tumor's origin; Of course, for most patients with significant biomarkers, the use of targeted small molecule kinase inhibitors also requires the use of approved indications, such as BRAF inhibitors (e.gvemurafenib, dabrafenib, encorafenib) that are very effective in melanomawiths with BRAF Val600Glu mutations, but for colorectal cancer with the same genetic mutation, the single drug treatment has the least effectFigure 2: Adult and child tumor spectrum with NTRK gene fusionhere to say "basket experiment", the so-called basket test, that is, regardless of the tumor site and pathological type, as long as the patient's tumor carries an iconic genetic mutation, recruit him to try a targeted drugFor example, to recruit all patients with ALK re-emission mutations to try the oxadine; to recruit all HER2 amplification patients to try herceptin; to recruit all patients with mTOR signaling pathway activation, to try ivemoles and so on - as long as they meet a certain gene mutation, they are caught in the basket, try the same target drugtargeting small molecules to unresolveddespite the presence of more than 500 protein kinases, only 5% of the approved targeted drugs, and most of these compounds are tyrosine kinase inhibitorsIt is now estimated that about 40 per cent of cancer patients have at least one mutation within the target range of the approved drug, while other kinases, which are in the role of cancer, have not yet been dug deep Further development of small molecule kinase inhibitors in the future includes better therapeutic indicators, better safety, better pharmacological properties, better entry (mainly the brain, spinal cord, testicles, etc.), and better resistance, and so on me-too/me-better drugs will remain the focus of current drug development and, with the greatest possible potential, to meet the current unmet clinical needs, it has to be said that the increase in effectiveness of me-too drugs is minimal and it would naturally make more sense to find more me-better EGFR inhibitors such as non-small cell lung cancer, gifitinib and urlotinib, are 4-aniline-based pyridine derivatives that can compete with ATP to bind to EGFR, thus blocking receptor activation and subsequent signal transduction Second-generation inhibitors, including afatinib, dacomitinib, and neratinib, have higher EGFR inhibition and irreversibly bind to the target, but also lead to higher incidence of skin and gastrointestinal toxicity while effectively inhibiting wild EGFR On this basis, three generations of inhibitors (e.g Ositinib) improved CNS permeability and had a wider coverage of EGFR mutants, with significant effects on EGFR allergization and EGFR Thr790Met mutations The fourth generation of inhibitors targeting three generations of drug-resistant mutations (i.e., those resistant to third-generation EGFR inhibitors, including osimertinib) are currently being studied, targeting the gene EGFR Cys797Ser, which has not yet been approved Figure 3: Treatment of NSCLC for T790M-EGFR mutations combination of drugs - the development of higher difficulty
global, small molecule kinase inhibitor combination, put a lot of investment, but not much successful lying.. For example, the mapK pathway for both BRAF and MEK blocking (e.g., dabrafenib and trametinib, vemurafenib and cobimetinib, encorafenib and binimetinib) can be used to treat the late-stage melanoma BRAF Val600 Glu mutation The treatment index of the combination of BRAF and MEK inhibitors is significantly better than its individual components, as the addition of MEK inhibitors may reduce some of the toxicity caused by the activation of the MAPK pathway caused by BRAF inhibition Figure 4: Examples of the dabrafenib-trametinib double inhibition schematic example 2, ibrutinib and venetoclax have been clinically proven to have complementary mechanisms for the treatment of chronic lymphocytic leukemia, and have shown higher effectiveness and better tolerance in two phase II studies published in 2019 The main challenge of combination therapy is to identify biomarkers so that patients can choose based on sensitivity and resistance to molecularly targeted drug combinations At the same time, the financial burden of combination therapy is very heavy, usually the cost of a single targeted treatment will lead to the inability to support the Future Development In the next decade, small molecule-targeted inhibitors will undoubtedly continue to play an important role in tumor treatment, and are currently trying to solve some of the outstanding problems With advances in molecular biology and drug AI, there are many ways to combine the development of targeted drugs The upgrading of non-clinical trial test models, as well as innovations in more rational clinical trial design, are also critical to accelerating the market for small molecules Only the innovation of science and technology and multidisciplinary joint innovation efforts, can be faster to bring small molecules to market! Reference: Lancet 2020; 395: 1078-88.
The Journal of Molecular Diagnostics, Vol 21, No 4, 2019.doi.org/10.1016/j.jmoldx.2019.03.008 Actaica Sinica Volume 40, pages268-278 (2019) the of The British Journal of Cancer.