The fourth generation of ALK inhibitor TPX-0131 made a stunning debut.

Recently, the American Association for cancer research (AACR) online annual meeting was held, which reported the global research and development of new drugs.Dr. Cui Jingrong of turning point therapeuti in the United States has released the preclinical data of tpx-0131, the fourth generation ALK inhibitor. Dr. Cui Jingrong is also the inventor of the first generation ALK targeting drug clazotinib.intergenerational inheritance of ALK targeted drugs_ Clazotinib, the first generation ALK inhibitor, is the first ALK inhibitor approved for the treatment of ALK + metastatic NSCLC._ The second generation ALK inhibitors, aletinib, seretinib and bugatinib, can overcome most of the resistance mutations of the first generation of clazotinib (such as g1269a and f1174l), but for kinase soluble region mutations, such as g1202r, it will cause universal resistance to the first and second generation ALK inhibitors._ Laratinib, the third generation ALK inhibitor, is sensitive to g1202r, but not to multiple drug resistant mutations (such as g1202r / l1196m).brief introduction of tpx-0131 tpx-0131 is a compact large ring structure, which is easy to combine with a series of housekeeper gene mutations, such as l1196 and g1202, and play its role in inhibiting wild-type and mutant ALK resistance mutations, including soluble region mutation (g1202r), gatekeeper mutation and compound mutation (Fig. 1).Figure 1: tpx-0131 has high sensitivity and obvious effect in combination with ALK. According to the reported data, tpx-0131 has high sensitivity to ALK wild type, ALK common mutation and various compound mutations, and the IC50 value is not higher than 6.6 (Table 1).Table 1 the activity of tpx-0131 kinase against wild-type and mutant ALK has lower IC50 value than other TKI for l1198f, g1202r, g1269a, and wild-type ALK (Table 2), which means that tpx-0131 of the fourth generation ALK has higher sensitivity and better effect on these targets, and may even affect the first-line, second-line and third-line drug distribution.however, it is worth noting that tpx-0131 is not ideal for i1171n, i1171s, i1171t and g1269s. On the contrary, the second and third generation alk-tki are more sensitive and effective (Table 2).Table 2 Comparison of tpx-0131 and approved ALK inhibitors for single mutation inhibition. Tpx-0131 is the most effective inhibitor for a series of EML4-ALK compound mutations, while the 1st, 2nd and 3rd generation ALK drugs show lower activity and sensitivity (Table 3).Table 3 Comparison of the ability of tpx-0131 and approved ALK inhibitors in inhibiting compound mutation. In addition, according to the mouse experimental study, in the tumor experiments with EML4-ALK g1202r refractory drug resistance, g1202r / l1198f and g1202r / l1196m compound mutation, tpx-0131 has the most obvious effect and the best effect on tumor at the dose of 10mg / kg twice a day (Fig. 2-4).Figure 2 the antitumor effect of tpx-0131 on EML4-ALK g1202r Figure 3 the anti-tumor effect of tpx-0131 on EML4-ALK g1202r / l1198f Figure 4 the antitumor effect of tpx-0131 on EML4-ALK g1202r / l1196m IV. conclusion tpx-0131, the fourth generation ALK inhibitor, is not only more sensitive in cell and animal experiments, but also has good therapeutic effect on refractory mutation and compound mutation.it brings new hope to ALK mutation patients with multi line resistance.we hope that researchers can speed up the research and let this targeted drug enter the human clinical trial stage as soon as possible, and the cancer degree will continue to be concerned.- --- reference materials: [1] code scanning consultation gene testing clinical recruitment and medical services