2. Academic Validation
  3. Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer

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

  • J Med Chem. 2021 Jul 22;64(14):10286-10296. doi: 10.1021/acs.jmedchem.1c00712.
Zongliang Liu 1,  Pengfei Yu 2,  Lin Dong 3,  Wenyan Wang 1,  Sijin Duan 3,  Bingsi Wang 3,  Xiaoyan Gong 3,  Liang Ye 2,  Hongbo Wang 1,  Jingwei Tian 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 2 Department of Clinical Medicine, Binzhou Medical College, Yantai 256603, China.
  • 3 Luye Pharma Group, Yantai 264005, China.
PMID: 34253025 DOI: 10.1021/acs.jmedchem.1c00712
Abstract

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 (LOXO-195) 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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