TPX-0005, a novel ALK/ROS1/TRK inhibitor, effectively inhibited a broad spectrum of mutations including solvent front ALK G1202R, ROS1 G2032R and TRKA G595R mutants

Cui, Jean; Zhai, Dayong; Deng, Wei; Rogers, Evan; Huang, Zheng‐Ming; Whitten, Jeffrey P.; Li, Y.

doi:10.1016/s0959-8049(16)32675-2

Cited by 28 publications

(20 citation statements)

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“…Recently a new ALK inhibitor, repotrectinib, was developed 30 . This compound has a compact three-dimensional macrocyclic structure that allows it to bind within the ATP binding pocket of different kinases, including ALK, ROS1 and pan-TRK to avoid steric hindrance from the mutations of the kinase solvent front residues 30,31 . The high affinity of repotrectinib towards the adenine-binding site of ATP allows it to block both wild type and various mutant ALK activities.…”

Section: Introductionmentioning

confidence: 99%

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells

Cervantes-Madrid

Szydzik

Lind

et al. 2019

Sci Rep

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Neuroblastoma is the most commonly diagnosed extracranial tumor in the first year of life. Approximately 9% of neuroblastoma patients present germline or somatic aberrations in the gene encoding for anaplastic lymphoma kinase (ALK). This increases in high-risk neuroblastomas, which have a 14% frequency of ALK aberrations at the time of diagnosis and show increasing numbers at relapse. Abrogating ALK activity with kinase inhibitors is employed as clinical therapy in malignancies such as non-small cell lung cancer and has shown good results in pediatric inflammatory myofibroblastic tumors and anaplastic large cell lymphomas. A phase I clinical trial of the first generation ALK inhibitor, crizotinib, in neuroblastoma patients showed modest results and suggested that further investigation was needed. Continuous development of ALK inhibitors has resulted in the third generation inhibitor repotrectinib (TPX-0005), which targets the active kinase conformations of ALK, ROS1 and TRK receptors. In the present study we investigated the effects of repotrectinib in a neuroblastoma setting in vitro and in vivo. Neuroblastoma cell lines were treated with repotrectinib to investigate inhibition of ALK and to determine its effect on proliferation. PC12 cells transfected with different ALK mutant variants were used to study the efficacy of repotrectinib to block ALK activation/signaling. The in vivo effect of repotrectinib was also analyzed in a neuroblastoma xenograft model. Our results show that repotrectinib is capable of inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and importantly it exhibits strong antitumor effects in a xenograft model of neuroblastoma.

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Section: Introductionmentioning

confidence: 99%

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells

Cervantes-Madrid

Szydzik

Lind

et al. 2019

Sci Rep

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“…Two next-generation TRK inhibitors (LOXO-195 and TPX-0005) are being tested in clinic to overcome these recur-rent resistance mutations. 32 , 33 The first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on another first-generation TRK-inhibitor, larotrec-tinib, received treatment with LOXO-195 and achieved rapid tumor responses and extended overall duration of disease control. 33 , 34 When trametinib was added to entrectinib, 1 patient with NTRK3 fusion-positive MASC harboring the solvent front mutation NTRK3 G623R in a post-entrectinib treatment biopsy achieved a 22% reduction in tumor volume and remained on the combination treatment for 6.7 months.…”

Section: Introductionmentioning

confidence: 99%

Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors

Liu

Offin

Harnicar

et al. 2018

TCRM

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Entrectinib is a potent small-molecule tyrosine kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1, and ALK. The consolidated results of 2 Phase I trials demonstrated activity in tyrosine kinase inhibitor-naïve patients along with substantial intracranial activity. In ROS1-rearranged lung cancers, entrectinib results in durable disease control and prolonged progression-free survival. The drug is well tolerated and has a safety profile that includes adverse events mediated by on-target tropomyosin-related kinase A/B/C inhibition.

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“…[162][163] (IC 50 = 0.0004 M), TRKB G639R (IC 50 = 0.0019 M) and TRKC G623R (IC 50 = 0.0004 M). 165 10 also exhibited activity in…”

Section: Second Generation Type I Trk Inhibitorsmentioning

confidence: 93%

“…xenograft tumor models bearing WT and kinase domain mutations of ALK, ROS1 and TRKA. [165][166] Other Type I TRK Inhibitors M, respectively) with selectivity in the greater kinome but also inhibited VEGFR2 (vascular endothelial growth factor receptor 2). [167][168] Compound 11 shares similarities in structure to other known VEGFR2 inhibitors, such as sunitinib, which likely accounts for its VEFGR2 profile.…”

Section: Second Generation Type I Trk Inhibitorsmentioning

confidence: 99%

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

et al. 2018

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The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

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TPX-0005, a novel ALK/ROS1/TRK inhibitor, effectively inhibited a broad spectrum of mutations including solvent front ALK G1202R, ROS1 G2032R and TRKA G595R mutants

Cited by 28 publications

References 0 publications

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells

Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of <em>NTRK</em>, <em>ROS1</em>, and <em>ALK</em> fusion-positive solid tumors

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

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