The tropomyosin receptor kinases (TRKs), including TRKA/B/C encoded by NTRK1/2/3 genes, are high-affinity receptors for neurotrophins. Oncogenic rearrangement of NTRK1, NTRK2, and NTRK3 have been identified in many solid malignancies. The use of TRK inhibitors entrectinib and larotrectinib has led to clinical benefit in patients with solid malignancies harboring oncogenic NTRK fusions. Similar to ALK and ROS1 inhibitor treatment, the solvent front mutations TRKA G595R and TRKC G623R (both analog to ALK G1202R) were reported in clinic from treatment-resistant patients. A new generation of TRK inhibitors targeting both wild type and mutated TRKs is highly needed for effectively treating patients harboring fusion TRKs. TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current TRK inhibitors in the clinic, was designed to overcome clinical resistance mutations systematically. TPX-0005 potently inhibited both wild type and mutant TRKs including solvent front mutations. TPX-0005 showed pico-molar activity against TRK kinases (IC50s 0.83 nM, 0.05 nM, and 0.10 nM for TRKA/B/C, respectively) in Reaction Biology kinase assay. TPX-0005 is the most potent TRK inhibitor in clinic and effectively overcomes clinical resistance TRK mutations as shown in the table in cell proliferation assays. It was recently reported that LOXO-195 inhibited the phosphorylation of TRKA and ERK kinases in NIH3T3 cell line expressing ΔTRKA G595R or ETV6-TRKC G623R with IC50s of 7 nM and 45.5 nM, respectively. TPX-0005 is more than 10-fold more potent than LOXO-195. In the xenograft tumor model studies including human PDX model, TPX-0005 dramatically caused tumor regression in the tumors carrying WT or solvent-front mutated TRK fusion gene. Overall, TPX-0005 demonstrated desired drug-like properties, good safety profile, and is a supreme TRK inhibitor against WT and mutated TRKs. A phase 1/2 clinical trial of TPX-0005 is actively being pursued (NCT03093116).

 KM-12 IC50 (nM) Ba/F3 Cell Proliferation Assay IC50 (nM) 
Inhibitor TPM3-TRKA
WT 		LMNA-TRKA WT LMNA-TRKA G595R ETV6-TRKB WT ETV6-TRKB G639R ETV6-TRKC WT ETV6-TRKC G623R 
TPX-0005 <0.2 <0.2 0.4 <0.2 0.6 <0.2 3 
Entrectinib 9.2 0.3 705 <0.5 1384 0.6 1000 
Larotrectinib 12.3 3.5 1024 10.9 3000 10.2 1500 
 KM-12 IC50 (nM) Ba/F3 Cell Proliferation Assay IC50 (nM) 
Inhibitor TPM3-TRKA
WT 		LMNA-TRKA WT LMNA-TRKA G595R ETV6-TRKB WT ETV6-TRKB G639R ETV6-TRKC WT ETV6-TRKC G623R 
TPX-0005 <0.2 <0.2 0.4 <0.2 0.6 <0.2 3 
Entrectinib 9.2 0.3 705 <0.5 1384 0.6 1000 
Larotrectinib 12.3 3.5 1024 10.9 3000 10.2 1500 
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Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John lim, Yishan Li. TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B184.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.