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J. Whitten



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.09 - ALK/ROS1/TRK Inhibitor TPX-0005 Effectively Overcomes Clinical Resistance Solvent Front Mutations (ID 8467)

      15:45 - 17:30  |  Author(s): J. Whitten

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK, ROS1 and TRK kinase inhibitors have achieved tremendous success in the treatment of lung cancer patients with abnormal ALK, ROS1 or NTRK gene. However, the emergence of drug resistance limits their long term clinical applications. An ever increasing number of acquired resistance mutations are being reported from the clinic. In addition to the gatekeeper mutations, the solvent front mutations have been recently recognized as common resistance mutations to many kinase inhibitors. For example, the solvent front ALK G1202R mutant conferred resistance to many clinical ALK inhibitors in lung cancer including crizotinib, ceritinib, alectinib, and brigatinib. The same position mutations ROS1 G2032R, TRKA G595R and TRKC G623R rendered resistance to the ROS1 inhibitor crizotinib in lung cancer, pan-TRK inhibitor entrectinib and larotrectinib in colon cancer, and larotrectinib in infantile fibrosarcoma, respectively.

      Method:
      A conserved glycine residue at the hinge C-terminal forms a hydrophobic sandwich with the kinase beta 1 sheet. Kinase inhibitors often use an aromatic ring or a flat motif to fit through this narrow glycine sandwich to the solvent. Alterations at the conserved glycine or the nearby residues, commonly referred to as solvent-front mutations, clash with the inhibitor motif and induce clinical resistance. Here, we designed TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ALK, ROS1, and TRK inhibitors in the clinic to avoid the steric clash inside the sandwich.

      Result:
      TPX-0005 resides at the center of the highly conserved ATP site without direct contact with the solvent front glycine sandwich. As expected, TPX-0005 potently inhibited WT EML4-ALK and solvent front mutant EML4-ALK G1202R with similar activities in both enzymatic (WT Ki 0.87 nM vs G1202R 0.81 nM) and Ba/F3 cell proliferation assays (WT IC~50~ 21.1 nM vs G1202R 20.5 nM). TPX-0005 showed potent activities against CD74-ROS1 G2032R (IC~50~ 8.4 nM), LMNA-TRKA G595R (IC~50~ 0.4 nM), TEL-TRKB G639R (IC~50~ 1.9 nM) and TEL-TRKC G623R (IC~50~ 0.4 nM) in Ba/F3 cell proliferation assays. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor growth inhibition and tumor regression in the tumors carrying WT and solvent-front mutations of ALK, ROS1 or TRKA fusion genes, respectively.

      Conclusion:
      Taken together, preclinical results demonstrated that TPX-0005 is a novel ALK/ROS1/TRK inhibitor overcoming the profound solvent front kinase mutations. TPX-0005 will bring new methods for the treatment of resistance patients with solvent front mutations in ALK, ROS1, or TRK fusion genes. A phase 1/2 study of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1) is actively pursued (NCT03093116).

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