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

At present, the market requirements 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 anti-tumor drugs are more concerned with TRK inhibitorsHowever, the two TRK inhibitors listed in 2018/2019 have developed in clinical development, although they have developed drug resistance problems, although they are of great concernThis article is to introduce the 1st generation of drugs on the basis of further introduction of the current development of 2 generations of 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 codingIn 1982, 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 TRK's biological function," (Photo Source: s41571-018-0113-0) 1The first drug on the market - larotinib Figure 1.2 Larotinib chemical structure semblet, 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 adults and pediatric patients with NTRK gene fusion rather than a specific type of cancerThree important clinical trials have been conducted for larotrectinib: the Adult Phase I Trial, the Paediatric I/II Trial (SCOUT) and the Adult/Adult Icent II Basket Trial (NAVIGATE), all of which have recruited patients with advanced solid tumorsFigure 1.3 Larotinib inhibition of TRKA/B/C, (image source) 22nd listed drug - Entrectinib Figure 1.4 Enquatinib Chemical Structure Enquatini, 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 source: ) Has 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, and thyroid cancerWhat are the problems with 2NTRK-1 generation drugs? The main problem, drug resistance! In addition, adverse reactions such as dizziness and mhesie disorders occur occasionally (as mentioned above)Drug resistance can be said to be the last undesirable phenomenon in the course of cancer treatment Today's drug treatment, once drug resistance, need to replace the drug immediately, 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 It has been found that NTRK inhibitors will have some resistance after treatment for a period of time (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; Similar TRKA-F589L, TRKB-F633L and TRKC-F617L;In addition, in terms of off-target resistance, it 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; For the problem of off-targeting, it is recommended to combine the drug combination of 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 samp; 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"; The 2nd generation of drugs has now been developed into the clinical stage, and some proof-of-concept information has been reported Figure 3.1 FDA-approved 1st generation drug and 2 generation TRK inhibitor comparison (picture source:) The drugs of the 2st generation of drugs selitrectinib and repotrectinib are characterized by: small molecular weight, large ring, can bind to at-ATP binding pockets, while avoiding spatial loss caused by mutations in the kinase domain;For solvent frontier mutations, the IC50 of selitrectinib and repotrectinib in enzyme assay are 2.0-2.3 nM and 2.7-4.5 nM, respectively For caerium residual mutations, the IC50 of sectinib and repotrectinib are 2.0-2.3 nM and .lt;0.2 nM, respectively For xDFG mutations, the IC50 of settinib and repotrectinib is 2.0-2.3 nM and 9.2 nM, respectively Figure 3.2 Seelitrectinib and Repotrectinib Clinical Representation Data on Chemical Structures: 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 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 Summary, through the introduction of two listed drugs and two generations of improved drugs, you can get a general understanding 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 Therefore, the author further statistics on 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: TRK Inhibitors Global In Research (Data from Pharmaceutical Crossing) References 1 Drug Crossing Data 2 Annals Of Oncology30 (Supplement 8): viii23-viii30, 2019 doi: 10.1093/annonc/mdz282 3 4 Lancet Oncol 2020 S1470-2045 (19)30856-3.