Trk Receptor Inhibitor

Entrectinib (NMS-E628) is an orally active, BBB-penetrated and centrally active inhibitor of TrkA/B/C, ROS1 and ALK, with IC₅₀ values of 1, 3, 5, 12 and 7 nM, respectively. Entrectinib induces apoptosis and cycle arrest in cancer cells, has antitumor activity, and attenuates bleomycin-induced lung fibrosis in mice.

Larotrectinib (LOXO-101) is an ATP-competitive oral, selective inhibitor of the tropomyosin-related kinase (TRK) family receptors, with low nanomolar 50% inhibitory concentrations against all three isoforms (TRKA, B, and C).

Repotrectinib (TPX-0005) is a potent ROS1 (IC₅₀=0.07 nM) and TRK (IC₅₀=0.83/0.05/0.1 nM for TRKA/B/C) inhibitor. Repotrectinib potently inhibits WT ALK (IC₅₀=1.01 nM). Repotrectinib has anti-cancer activity.

TrkA/NGF-IN-1 (Peptide 19) is an inhibitor of protein-protein interactions between TrkA and NGF (IC₅₀: 21 nM for human TrkA in PathHunter assay). TrkA/NGF-IN-1 shows an analgesic effect in a rat incisional pain model.

TrkA-IN-5 is a TrkA inhibitor with an IC₅₀ value of 1.678 nM against TrkA. TrkA-IN-5 can be used in cancer research.

DS002 is a human monoclonal antibody targeting NGF/bNGF, with an IC₅₀ of 6.60 nM against human NGF, 1.98 nM against rat NGF, and 8.46 nM against mouse NGF. DS002 blocks NGF-TrkA binding, interrupts pain signal transduction, inhibits TrkA-mediated downstream signaling pathways, and alters aromatic amino acid metabolic pathways. DS002 inhibits cancer cell proliferation. DS002 exerts a preventive effect on Paclitaxel-, Cisplatin- and Vincristine-induced peripheral neuropathy in rats. DS002 can be used in studies related to chronic pain and chemotherapy-induced peripheral neuropathy.

GW 441756 is a potent and specific nerve growth factor (NGF) receptor tyrosine kinases A (TrkA) inhibitor (IC₅₀=2 nM), which eliminates the BmK NSPK-induced neurite outgrowth.

K-252a, a staurosporine analog, inhibits protein kinase, with IC₅₀ values of 470 nM, 140 nM, 270 nM, and 1.7 nM for PKC, PKA, Ca²⁺/calmodulin-dependent kinase type II, and phosphorylase kinase, respectively. K-252a is a potent inhibitor (IC₅₀ of 3 nM) of the tyrosine protein kinase (TRK) activity of the NGF receptor gp140trk, the product of the trk protooncogene.

Sitravatinib (MGCD516) is an orally bioavailable receptor tyrosine kinase (RTK) inhibitor with IC₅₀s of 1.5 nM, 2 nM, 2 nM, 5 nM, 6 nM, 6 nM, 8 nM, 0.5 nM, 29 nM, 5 nM, and 9 nM for Axl, MER, VEGFR3, VEGFR2, VEGFR1, KIT, FLT3, DDR2, DDR1, TRKA, TRKB, respectively. Sitravatinib shows potent single-agent antitumor efficacy and enhances the activity of PD-1 blockade through promoting an antitumor immune microenvironment.

Cyclotraxin B is a BBB-penetrable and selective TrkB inhibitor. Cyclotraxin B inhibits BDNF-induced TrkB activity in a non-competitive manner, with an IC₅₀ of 0.30 nM. Cyclotraxin B has analgesic and anxiolytic effects.

Selitrectinib (LOXO-195) is a next-generation TRK kinase inhibitor, with IC₅₀s of 0.6 nM and <2.5 nM for TRKA and TRKC, respectively.

GNF-5837 is a potent, selective, and orally bioavailable pan-tropomyosin receptor kinase (TRK) inhibitor which display antiproliferative effects in cellular Ba/F3 assays ( IC₅₀ values of 7 nM, 9 nM and 11 nM for cells containing the fusion proteins Tel-TrkC, Tel-TrkB and Tel-TrkA, respectively) .

Lestaurtinib (CEP-701) is an orally active and selective RPTKs (receptor protein tyrosine kinase) inhibitor, competitively inhibits ATP binding to the TrkA/B/C domain. Lestaurtinib inhibits RPTKs phosphorylation, with IC₅₀s of 2, 25 and 0.9 nM for FLT3, TrkA and JAK2, respectively. Lestaurtinib induces apoptosis and cycle arrest, also can inhibit growth of tumor.

Altiratinib (DCC-2701) is a multi-targeted kinase inhibitor with IC₅₀s of 2.7, 8, 9.2, 9.3, 0.85, 4.6, 0.83 nM for MET, TIE2, VEGFR2, FLT3, Trk1, Trk2, and Trk3 respectively.

Bedinvetmab (ZTS-00508841) is a canine monoclonal antibody (mAb) targeting nerve growth factor (NGF). Bedinvetmab inhibits NGF interaction with tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR) receptors. Bedinvetmab can be used for the research of osteoarthritis pain in dogs.

Larotrectinib sulfate (LOXO-101 sulfate; ARRY-470 sulfate) is an ATP-competitive oral, selective inhibitor of the tropomyosin-related kinase (TRK) family receptors, with low nanomolar 50% inhibitory concentrations against all three isoforms (TRKA, B, and C).

Tamnorzatinib (ONO-7475) is a potent, selective, and orally active Axl/Mer inhibitor with IC50 values of 0.7 nM and 1.0 nM, respectively. Tamnorzatinib sensitizes AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs, suppresses the emergence and maintenance of tolerant cells. Tamnorzatinib combines with Osimertinib (HY-15772) provides a bright promise for the study of EGFR-mutated non-small cell lung cancer (NSCLC).

Tyrphostin AG 879 (AG 879) is a tyrosine kinase inhibitor that inhibits TrKA phosphorylation (IC₅₀ of 10 μM), but not TrKB and TrKC. Tyrphostin AG 879 is also a selective ErbB2 tyrosine kinase inhibitor with an IC₅₀ of 1 μM, and has at least 500-fold higher selectivity to ErbB2 than EGFR. Tyrphostin AG 879 has anticancer activity.

AZ-23 is an ATP-competitive and orally bioavailable Trk kinase A/B/C inhibitor with IC₅₀s of 2 nM (TrkA), 8 nM (TrkB), 24 nM (FGFR1), 52 nM (Flt3), 55 nM (Ret), 84 nM (MuSk), 99 nM (Lck), respectively.

Belizatinib (TSR-011) is an orally active, potent inhibitor of ALK and TRKA, TRKB, and TRKC, with IC₅₀ of 0.7 nM for wild-type recombinant ALK kinase.