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Molecular Cancer Therapeutics
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Therapeutic Agents: Small-Molecule Kinase Inhibitors

Abstract B184: TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R

J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John lim and Yishan Li
J. Jean Cui
TP Therapeutics, Inc., San Diego, CA.
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Dayong Zhai
TP Therapeutics, Inc., San Diego, CA.
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Wei Deng
TP Therapeutics, Inc., San Diego, CA.
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Evan Rogers
TP Therapeutics, Inc., San Diego, CA.
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Zhongdong Huang
TP Therapeutics, Inc., San Diego, CA.
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Jeffrey Whitten
TP Therapeutics, Inc., San Diego, CA.
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John lim
TP Therapeutics, Inc., San Diego, CA.
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Yishan Li
TP Therapeutics, Inc., San Diego, CA.
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DOI: 10.1158/1535-7163.TARG-17-B184 Published January 2018
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Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA

Abstract

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)
InhibitorTPM3-TRKA
WT
LMNA-TRKA WTLMNA-TRKA G595RETV6-TRKB WTETV6-TRKB G639RETV6-TRKC WTETV6-TRKC G623R
TPX-0005<0.2<0.20.4<0.20.6<0.23
Entrectinib9.20.3705<0.513840.61000
Larotrectinib12.33.5102410.9300010.21500

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.
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Molecular Cancer Therapeutics: 17 (1 Supplement)
January 2018
Volume 17, Issue 1 Supplement
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Abstract B184: TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R
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Abstract B184: TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R
J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John lim and Yishan Li
Mol Cancer Ther January 1 2018 (17) (1 Supplement) B184; DOI: 10.1158/1535-7163.TARG-17-B184

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Abstract B184: TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R
J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John lim and Yishan Li
Mol Cancer Ther January 1 2018 (17) (1 Supplement) B184; DOI: 10.1158/1535-7163.TARG-17-B184
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Therapeutic Agents: Small-Molecule Kinase Inhibitors

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  • Abstract B147: A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors
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Therapeutic Agents: Small-Molecule Kinase Inhibitors: Poster Presentations - Proffered Abstracts

  • Abstract B177: Synthetic lethal approach identifies potent and selective TTK and CLK inhibitor with preclinical anticancer activity in triple-negative breast cancer model
  • Abstract B147: A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors
  • Abstract B152: CB1763, a highly selective, novel non-covalent BTK inhibitor, targeting ibrutinib-resistant BTK C481S mutant
Show more Therapeutic Agents: Small-Molecule Kinase Inhibitors: Poster Presentations - Proffered Abstracts
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Molecular Cancer Therapeutics
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