Assessment of the toxicity and toxicokinetics of the novel potent tropomyosin receptor kinase (Trk) inhibitor LPM4870108 in rhesus monkeys

Duan, Sijin; Dong, Lin; Wang, Bingsi; Wei, Shujuan; Gong, Xiaoyan; Yu, Pengfei; Li, Chunmei; Gao, Yonglin; Liang, Y. T.; Wang, Hongbo; Tian, Jingwei

doi:10.1016/j.yrtph.2021.104886

Cited by 2 publications

(2 citation statements)

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“…In our previous 4 weeks of repeated administration toxicity study in Cynomolgus monkeys, treatment-related changes included gait disturbance, impaired balance, and poor coordination, which could be attributed to excessive on-target Trk receptor inhibition. In addition, no significant changes in food consumption, electrocardiogram, blood pressure, hematological and biochemical parameters, organ weight, or bone marrow parameters were observed . All these data suggest that compound 10 was more efficacious and safer against tumor growth than LOXO-195 (Table ).…”

Section: Results and Discussionmentioning

confidence: 99%

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Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer

Liu

Dong

et al. 2021

J. Med. Chem.

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The neurotrophic receptor tyrosine kinase (NTRK) genes including NTRK1, NTRK2, and NTRK3 encode the tropomyosin receptor kinase (Trk) proteins TrkA, TrkB, and TrkC, respectively. So far, two TRK inhibitors, larotrectinib sulfate (LOXO-101 sulfate) and entrectinib (NMS-E628, RXDX-101), have been approved for clinical use in 2018 and 2019, respectively. To overcome acquired resistance, next-generation Trk inhibitors such as selitrectinib and repotrectinib (TPX-0005) have been developed and exhibit effectiveness to induce remission in patients with larotrectinib treatment failure. Herein, we report the identification and optimization of a series of macrocyclic compounds as potent pan-Trk (WT and MT) inhibitors that exhibited excellent physiochemical properties and good oral pharmacokinetics. Compound 10 was identified via optimization from the aspects of chemistry and pharmacokinetic properties, which showed good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies.

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Section: Results and Discussionmentioning

confidence: 99%

“…In addition, no significant changes in food consumption, electrocardiogram, blood pressure, hematological and biochemical parameters, organ weight, or bone marrow parameters were observed. 16 All these data suggest that compound 10 was more efficacious and safer against tumor growth than LOXO-195 (Table 4).…”

Section: ■ Introductionmentioning

confidence: 95%