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    Home > Medical News > Latest Medical News > The light is covered by ALK. How can ROS1 inhibitors get out of their own future?

    The light is covered by ALK. How can ROS1 inhibitors get out of their own future?

    • Last Update: 2020-07-29
    • Source: Internet
    • Author: User
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    ROS1 has been one of the most interesting targets in recent years, and has been studied in many tumor fields, especially in the most extensive field of lung cancerHowever, when it comes to ROS1, it will lead to ALK, and several listed ALK inhibitors have been validated in the ROS1 direction, and the efficacy of ROS1 inhibitors seems to be forever obscured by ALKSo, ROS1, ROS1 gene fusion, and its inhibitors, to what stage of current development? How can ROS1 inhibitors get out of their own future? Please look at this manuscriptROS1 fusion gene positive introduction ROS1 fusion gene positive, originally found in 1987, and then found in 2007 in non-small cell lung cancer patients, then in the nSCLC field more research; A 2014 joint guidelines from the American College of Pathologists, the International Association for The Study of Lung Cancer and the Society for Molecular Pathology recommend edified for ROS1 testing in all patients with advanced lung adenocarcinoma, regardless of clinical characteristicsFigure 1.1: ROS1 - Important Representative Event Timeline (Photo: Journal of Oncology Vol12 No11: 11: 1611-1625) THE ROS1 gene is sensitive to chromosomal arrangement, leading to gene fusion involving the ROS1 tyrosine kinase domain, the product of which is an effective carcinogenic driverAbnormal activation of ROS1 fusion proteins activates several downstream signal transduction pathways, including: RAS-RAF-MEK-MAPK, PLC/IP3, SHP2/VAV3, JAK-STAT3, and PI3K-AKT-mTOR downstream signaling pathwaysAfter ROS1 activation, phosphorylation occurs in the 2274 and 2334 thoratosin residues of the kinase domain, and promotes the activation of downstream substrate proteins, thus promoting the proliferation and transformation of tumor cellsAt present, the expression of ROS1 gene fusion can be seen in many tumor cells, such as malignant glioma, non-small cell lung cancer, liver cancer, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibromablastoma, malignant hemopathy nephritoma and so onFigure 1.2: ROS1 Gene fusion-positive downstream pathways (Photo: doi.org/10.1016/B978-0-12-801238-3.11702-7) ALK ROS1: Homogenical? When it comes to ROS1, avoid ALKALK is an important target for lung cancer, with several drugs on the market and has been developed for four generationsIt has been reported that the ALK and ROS1 kinase region sequences have 49% homologous, at ATP binding sites have up to 77% homologous, and most of the differences occur in conservative regions, so this may be the vast majority of ALK inhibitors can simultaneously inhibit the proliferation of ROS1-positive cell lines and effective for PATIENTs with ROS1-positive lung cancerSince ALK was discovered and developed earlier than ROS1, most of the drugs listed in the relevant market are used in clinical use as ALK, and ROS1 has almost become an accessory to the development process (of course, it is now a mandatory), inhibitors are also mostly non-selective drugs, and the real ROS1 selective drugs, there is no outstanding substantive characteristics and significant progressFigure 2.1: For example, The Ctutinib acts on ALK and ROS1 (Source:) Listed ROS1 Inhibitors To date, Crizotinib, Ceritinib, Brigatinib, Cabozantinib, Lorlatinib, Entrectinib and Repotctinib have been clinically effective in The NSCLC, which is positive for THE integration of the ROS1 geneFigure 3.1: Listed ROS1 represents the interaction of drugs and targets (Figure: doi.org/doi: 10.1016/j.phrs.2017.04.022) Example: gramafenib, the first listed ROS1 inhibitor, first as alK, c-Met radical seine inhibitorsClinical studies PROFILE1001 confirmed the sensitivity of the NSCLC cell line of ROS1 rearrangement to creditinib, and the Phase I study and subsequent prospective and retrospective studies confirmed the clinical efficacy of keratosinin in patients with ROS1 rearrangement in tumors After completing a series of clinical trials, the FDA approved keroctinib for the treatment of patients with advanced ROS1-positive NSCLC, which was subsequently recommended as a first-line treatment Figure 3.1: ROS1 Gene Fusion Positive NSCLC uses different TKI clinical trial comparisons (photo source: doi.org/10.1016/j.thorsurg.2020.01.007) Future development direction: Selective ROS1 inhibitors to truly reveal the advantages of ROS1 in target and drug-based, selective inhibitors of its own But so far, no ROS1 selective inhibitors have entered clinical development. However, some nM-grade compounds have been reported (such as a class of "di-aromatic pyridine derivatives" reported abroad) and the selectivity of ALK is hundreds of times higher, and its related reports deserve follow-up attention And the development of selective ROS1 inhibitors, in addition to try to "avoid" ALK, in recent years a very hot target NTRK, must also pay attention to, and many related listed and in-research drugs have NTRK/ ALK/ROS1 as a whole, as a must research project! Such as the 2019 listing of Entitini, clinical dS-6051, Repotrectinib, HG-030, and so on Further introduction of DS-6051 and HG-030, are now domestic development DS-6051, is an exclusive introduction of the variety from Japan's First Sangong Co., Ltd., ros1 and NTRK dual-target inhibitors, has been released in "Communications Nature" important development information, and Chengdu pilot development of HG-030 for the second generation nt oral small molecular inhibitors, is also ROS1 and NTRK dual target inhibitors Relatively speaking, the domestic development of ROS1 targets, the above two varieties are worthy of attention to track Finally, the global development statistics of ROS1 inhibitors are attached to the end of the text for a panoramic understanding of the target-related drugs Attached: Global ROS1 Inhibitor High Stage Development Statistics Statistics References: 1.Journal of Thoracic Oncology Vol 12 No 11: 1611-1625 2.Thorac Surg Clin 30 (2020) 147-156 3 Encyclopedia of The SanE Medicine, 2nd Edition 4.Ixical Research 5.Newport/Pharmaprojects Date.
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