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

The ALK mutation is called the "diamond mutation" of lung cancer, which has reached a long-term chronic condition under the sequential use of various generation-targeted drugs.
at present, alK target drugs have a generation of keratinib, second-generation Ceridesini, Bugatini and Alatini, three generations of Loratini.
but targeted treatment can not escape the plight of drug resistance, the urgent need for the fourth generation of targeted drugs.
released preclinical data on the fourth generation of alK inhibitor TPX-0131 at the second session of AACR, which has just been held, offering new hope for patients with ALK mutations.
TPX-0131 cracked drug resistance mechanism ALK G1202R mutation is one of the most important drug resistance mechanisms of first and second generation ALK inhibitors.
third-generation ALK inhibitors are effective against ALK G1202R, but in vitro experiments and patient resistance data show that a variety of ALK compound mutations are the main drug resistance mechanism.
TPX-0131 is a compact large ring structure that facilitates insertion into adenosine binding pockets with clear boundaries with the L1196 and G1202.
from the drug dosage form, Laura Tini is small and still sensitive to mutations such as G1202R, while the TPX-0131 has a compact large ring design that fits into adenosine binding pockets and covers a series of mutations from the gatekeeper l1196 to G1202, which inhibit wild and mutant ALK resistance mutations.
preclinical data show that TPX-0131 has a high sensitivity to ALK wild types, common ALK mutations, and various types of co-formation mutations.
IC50 value is no higher than 6.6.
. In 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 rankings.
live studies to further validate cellular data.
in mice with eML4-ALK G1202R refractive resistance, G1202R/L1198F and G1202R/L1196M co-emerging mutant cell-derived allogeneic transplanted mouse tumors, with TPX-0131 showing clear resistance to tumors when treated with tPX-0131 at a two-dose dose of 10 mg/kg per day.
studies show that TPX-0131 has clear biological, cellular, and inviviable activity for G1202R, L1196M, G1202R/L1196M and G1202R/L1198F complex mutations.
bring new options to curb ALK resistance.
In addition to TPX-0131, there is another fourth-generation ALK inhibitor that is expected to be born -- TPX-0005.
TPX-0005 (Repotrectinib Ripotini) is an oral fourth generation ALK inhibitor developed by TP Therapeutics that can be effective against acquired mutationAL G1202R.
TPX-0005 is designed to effectively bind active kinase conformation and avoid spatial interference caused by various clinically resistant mutations.
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 kinases.
According to research, the third generation of drug resistance often appears after two more site mutations, and the past ALK inhibitors only for a single-point mutation, which makes the first generation, second generation, three generations of drugs ineffective.
and the fourth-generation drug Ripotinib is strong, it can effectively inhibit a large number of ALK site mutations, especially the clinically observed G1202R, L1196M and other complex mutations.
, there may also be better inhibition effects on wild ALK mutations and other nSCLC synotypes.
previous studies have found that Srckinase promotes cancer cell migration, adhesion and proliferation, and is one of the "killers" of patients who are resistant to ALK inhibitors.
currently based on preclinical trials, Ribotinib is also an effective Src inhibitor that inhibits cancer cell growth and metastasis from another angle.
it 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 cancer cell metastasis.
multiple ALK inhibitors will continue to develop in 2020, and will bring more effective data to address efficacy, drug resistance and other issues for Patients with ALK mutations, and we will continue to report on the progress of relevant research.
Reference Source: 1. 2. 3. 3. Lair ALK Kats Can Select for The Alorlatinib-Resistant For Alksanib-Resistant For AlK Mutations in ALK-Positive Lung Lung Cancer 4.Scientific Reports, Diana Cervantes-Madrid, Repotrectinib (TPX-0005), Efectively Ally Sr.