Now and in the Future: 4 Varieties Of Panorama Describes "God Drug-TRK Inhibitors"

TextJohnson's current demand for drugs, is no longer satisfied with a single drug single target single disease, broad-spectrum, effective, safe, more compliance of the drug, for clinical urgent needPD-1 inhibitors are undoubtedly milestones in the discovery of macromolecule biopharmaceuticals in the field of tumors in recent years, while small moleculebroad-spectrum anti-tumor drugs are more concerned with TRK inhibitorshowever, the two TRK inhibitors listed in 2018/2019, although the attention is greater, but has appeared drug resistance problems, for this, the 2st generation of drugs have entered clinical developmentthis article is to introduce the 1st generation of drugs on the basis of further introduction of the current development of 2 generation drugs, with a view to 4 drug development status, so that readers quickly understand the pan-cancer treatment drug TRK inhibitors now and in the future! 1NTRK and 2 generation 1 drugs listed, neurotrophin receptor tyrosine kinase (Neuro Trophin Receptor Kinase), consisting of highly homologous kinase TRK-A, TRK-B, TRK-C, belong to the NTRK gene coding1982, the kinase TRK-A was identified in two colon cancer patients; although TRK was initially identified in tumor transformation, the family was generally distributed in the nervous system and highly associated with neurodevelopment (PS: adverse reactions were also associated with it), while the TRK series was also encoded as TRK-ARK-A, TRK-B and TRK-CRKFigure 1.1: Key advances in The Biological Function of TRK(Image Source: s41571-018-0113-0) 1The first drug on the market - larotinib Figure 1.2 Larotinib chemical structure originally, Janne and Doebele et al., reported finding larotrectinib, a pan-TRK inhibitor, whose IC The value of 50 is between 2-20 nM and has good selectivity on other kinases (statistically, more than 100 times the selectivity of 229 other kinases and more than 1000 times the selectivity of 80 non-kinase targets)approved by the FDA in 2018 (product name: Vitrakvi) for the treatment of adult sororcinomas with NTRK gene fusion rather than specific types of cancerhas conducted three important clinical trials for larotrectinib: the Adult Phase I Trial, the Paediatric Phase I/II Trial (SCOUT) and the Adult/Adult Icent II Basket Trial (NAVIGATE), all of which recruited patients with advanced solid tumorsFigure 1.3 Larotinib inhibition of TRKA/B/C, (picture source) 22nd listed drug - Entrectinib Figure 1.4 Enquatinib chemical structure entitinib, unlike larotinib, is a multikine inhibitorin addition to TRKA/B/C, it inhibits ROS1 and ALKsuch as NTRK fusion-positive KM12 cell line, ROS1 fusion CUTO-27 cell line, ALK fusion NB-1 cell line, etcFigure 1.5 Enctinib's partial inhibition statistics on different types of cancer in different cell lines (Picture: :) Have conducted four important clinical trials for entrectinib: the Adult Phase I Trial (ALKA-372-001, Italy); Phase I Trials (STARTRK-1, Global); Phase II Clinical Trials (STARTRK-2);Figure 1.6 For example: Enquatini-STARTRK-2 basket of experimental research programmes (photo source:) the above-listed two drugs that can treat a variety of types of tumors, including four histological forms rich due to NTRK gene fusion (breast analoguous secretion cancer, secretion breast cancer, pediatric fibroid sarcoma and congenital mid-embryo kidney tumors), as well as several other malignancies, including lung cancer, gastrointestinal cancer, breast cancer and thyroid cancerWhat are the problems with the 2NTRK-1 drug in ? The main problem, drug resistance! In addition, adverse reactions such as dizziness and mhesie disorders occur occasionally (as mentioned above) drug resistance problem, can be said to be the last undesirable phenomenon in the course of cancer treatment current drug treatment, once drug resistance, need to immediately replace the drug, and often a batch of drugs can not be used, if there is an iterative drug use is good, if not, the patient's condition will quickly deteriorate can not be controlled has now found that NTRK inhibitors will have a certain resistance phenomenon after treatment (mainly related to NTRK1/NTRK3), and further studies have found that the occurrence of the domain mutation is similar to the mutation of ALK, ROS1 kinase; solvent frontier site mutations include TRKA-G595R, TRKB-G639R and TRKC-G623R, similar to ALK-G1202R and ROS1-G2032R; M similar TRKA-F589L, TRKB-F633L and TRKC-F617L; , in terms of off-target resistance, is also similar to ALK and ROS1 fusion positive, and has been found in TRK fusion-positive cancer patients' tumors and plasma samples related to KRAS-MET amplification, BRAF-V600E mutation, and KRAS mutation; and for off-targeting, it is recommended to combine tRK and related kinase inhibitors to combat resistance to 1 generation of drugs! Figure 2.1 Drug Resistance and Off-Target Information for Generation 1 TRK Inhibitors (Photo Source: s41571-018-0113-0) 3NTRK s Generation 2 drugs represent the varieties of selitrectinib and repotrectinib first, the 2nd generation Of TRK inhibitors are designed in the direction of "anti-mutation/off-target resistance while maintaining the inhibition of TRKA/B/C"; 2 generations of drugs have now been developed into the clinical stage, and some proof-of-concept information has been reported Figure 3.1 FDA-approved 1 statinib and 2 generations of TRK inhibitorcomparisoncomparisoncomparisons (picture source: 2 generations of drugs selitrectinib and repotrectinib are characterized by: small molecular weight, large ring, can bind to ATP bound pockets, while avoiding spatial loss caused by kinase domain mutations; ic50 of selitrectinib and repotrectinib in enzyme assay are 2.0-2.3 nM and 2.7-4.5 nM, respectively, for solvent frontier mutations ic50 of seelitrectinib and repotrectinib is 2.0-2.3 nM and .lt;0.2 nM, respectively ic50 for xDFG mutations, seelitrectinib and repotrectinib are 2.0-2.3 nM and 9.2 nM, respectively Figure 3.2 Representative Data on the Clinical Aspects of Chemical Structures of Seelitrectinib and Repotrectinib: Nature Review introduces 31 cases (of which 20 patients were from THE LOXO-195 Phase I clinical trial, and 11 patients were from the Sympathetic Drug Program and the previous NTRK Targeting Drug Treatment of median duration of 9.5 months) TRK fusion-positive cancer patients (all treated with previous TRK inhibitors (larotrectinib, entrectinib or PLX7486) received selitrectinib treatment, the most likely solvent frontier mutation patients with objective remission rate of 45% ORR Figure 3.3 Selitrectinib Partial Clinical Trial Information (Picture Source: Drug Data) 4 End-of-text Egg Synthesis, through the introduction of two listed drugs and two generations of improved drugs, you can get a rough idea of the development of pan-cancer TRK inhibitors foreign development is in full swing at the same time, the domestic is actually gradually catching up, and many 2 generations of drugs have been approved clinically, only a little slower in progress as a pan-cancer treatment drug, domestic and foreign naturally will not miss this the author further statistics the global development of TRK inhibitors at the end of the article, so that we can better understand the panoramic competitive pattern of the target schedule of : TRK inhibitors global in research (data derived from drug crossing) Reference 1 Drug ferry data 2 Annals Of Oncology30 (Supplement 8): viii23-viii30, 2019 doi: 10.1093/annonc/mdz2823 Lancet Oncol 2020 S1470-2045 (19)30856-3.