TPX-0005 is a potent ATP-competitive multiple-target inhibitor against ALK, ROS1, TRKA, TRKB and TRKC recombinant kinases and their corresponding clinical resistant mutants, as well as SRC, with IC50 values of 1.01nM, 1.26nM, 1.08nM and 5.3nM for WT ALK, ALKG1202R, ALKL1196M and SRC, respectively. Compared with the current ALK inhibitors, TPX-0005 possesses a novel three-dimensional macrocycle with a much smaller size. TPX-0005 exhibited potent anti-proliferative activity against a number of cell lines with IC50 values of subnanomolar or nanomolar, accompanied by inhibition of target phosphorylation and concomitant inactivation of downstream effectors such as ERK, AKT and STAT3. Treatment with TPX-0005 resulted in significant regression of tumors harboring the oncogenic ALK, ROS1 and TRKC fusions of patient derived xenograft tumor models[1][2]. Oral administration of TPX-0005, twice daily, led tumor growth inhibition of 197% and 200% against CD74–ROS1 WT tumors and 99% and 200% against CD74–ROS1G2032R tumors, at dose of 15 or 75mg/kg (crystalline form), respectively, in SCID/Beige mice. Also, when dosed in a micronized crystalline formulation, TPX-0005 resulted in tumor growth inhibition of 100% and 128% against NIH3T3 LMNA–TRKA WT tumors at dose of 3 and 15 mg/kg, respectively, as well as 56%, 97% and 123% against TRKAG595R tumors at dose of 3, 15, or 60 mg/kg in athymic nude mice. This TGI by TPX-0005 could also be observed in SCID/Beige mice bearing Ba/F3 EML4–ALK v1 WT or EML4–ALK v1 G1202R xenograft tumors at dose of 15 or 75 mg/kg[3].
作用机制
TPX-0005 is an ATP-competitive inhibitor designed to efficiently target the center of the ATP binding site and circumvent the steric interference from mutations outside the ATP binding boundary.[1]
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