The fourth generation of ALK inhibitors appear to crack the lung cancer "diamond" mutation resistance problem.

The ALK mutationthe alK mutation of the chinese medicine is called the "diamond mutation" of lung cancer, and has reached the state of chronic disease sane disease under the sequential use of various generation-targeted drugsAt present, the ALK-targeted drug has a generation of ketriatini, second generation ceritini, bugatini and Alatini, three generations of LoratiniBut targeted treatment can not escape the plight of drug resistance, the urgent need for the fourth generation of targeted drugsPreclinical data on the fourth generation of alK inhibitor TPX-0131 were released at the second session of AACR, which has just been held, offering new hope for patients with ALK mutationsALK G1202R mutation is one of the most important drug resistance mechanisms of first and second generation ALK inhibitorsAlthough the third generation of ALK inhibitors is effective for ALK G1202R, in vitro tests and patient resistance data show that a variety of ALK compound mutations are the main drug resistance mechanismTPX-0131 is a compact large ring structure that facilitates insertion of adenosine binding pockets with clear boundaries with L1196 and G1202In terms of drug dosage form, The loradeni is small and can still be sensitive to mutations such as the G1202R, while the TPX-0131 has a compact large ring design that fits into adenosine binding pockets, covering a series of mutations from the gatekeeper l1196 to G1202, which inhibit wild and mutant ALK resistance mutations1Preclinical data show that TPX-0131 is highly sensitive to ALK wild types, common ALK mutations, and various co-developing mutationsThe IC50 value is no higher than 6.6In all types of mutations, TPX-0131 has a lower IC50 value than other TKI ic50 values for L1198F, G1202R, G1269A, and wild ALK compared to the previously approved first three generations of ALK drugs, indicating the potential priority of the fourth generation alK 0131 at these targets, which may affect the first, second and third-line drug rankingslive studies to further validate cellular datain mice with cell-derived allogeneic transplants with mhemogenic mutations in EML4-ALK G1202R, G1202R/L1198F and G1102R/L1196M co-emerged mutant serotonin, showing clear resistance to tumors when treated with TPX-0131 at a two-dose dose of 10 mg/kg per daystudies show that TPX-0131 has clear biological, cellular, and inviviable activity for G1202R, L1196M, G1202R/L1196M and G1202R/L1198F complex mutationsNew options are offered to curb ALK resistanceIn addition to TPX-0131, there is another fourth-generation ALK inhibitor that is expected to be born -- TPX-0005TPX-0005 (Repotrectinib Ripotinib) is an oral fourth generation ALK inhibitor developed by TP Therapeutics that can be effective against acquired mutationAL G1202RTPX-0005 is designed to effectively bind active kinase conformation and avoid spatial interference caused by various clinically resistant mutationsThe compact and rigid three-dimensional structure allows Repotrectinib to accurately and effectively penetrate the ATP binding sites of kinases and potentially avoid spatial interference, leading to resistance to larger kinase inhibitors, especially ALK kinasesAccording to research, the third generation of drug resistance often appears after two more than site mutations, and the past ALK inhibitors only for single-point mutations, which makes the first generation, second generation, three generations of drugs ineffectiveThe fourth-generation drug Ripotinib is very strong, it can effectively inhibit a large number of ALK site mutations, especially the clinically observed G1202R, L1196M and other compound mutationsIn addition, wild alK mutations and other nSCLC synotypes may also have a better inhibitory effectprevious studies have found that Srckinase promotes cancer cell migration, adhesion and proliferation, and is one of the "killers" of patientresistance to ALK inhibitorsCurrently, according to preclinical trials, ribotinib is also an effective Src inhibitor that inhibits cancer cell growth and metastasis from another angleit appears that the fourth-generation drug ripotinib can not only effectively solve the problem of drug resistance after the first, second and third generations of drugs, compared with the first three generations of ALK inhibitors, it also has a significant advantage in inhibiting the metastasis of cancer cellsmore ALK inhibitors will continue to develop in 2020, will also bring more effective data for ALK mutation of NSCLC patients to solve efficacy, drug resistance and other issues, we will continue to report on the relevant research progress.