TrkA Inhibitor

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.

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.

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.

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.

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.

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.

PF-6683324 (Trk-IN-4) is a potent pan-Trk inhibitor in cell-based assays with IC₅₀s of 1.9 nM, 2.6 nM and 1.1 nM for TrkA, TrkB and TrkC, respectively. Anti-hyperalgesic effect.

PF-06273340 is a peripherally restricted pan-Trk inhibitor with IC₅₀ values of 6, 4, 3 nM for TrkA, TrkB, and TrkC receptors. PF-06273340 binds in a DFG-out conformation, targeting less conserved kinase ligand binding domain regions outside the ATP binding pocket. PF-06273340 exhibits anti-hyperalgesic and analgesic effects. PF-06273340 can be used for the research of pain.

TrkA-IN-3 is a potent, subselective and allosteric TrkA inhibitor, with an IC₅₀ of 22.4 nM. TrkA-IN-3 shows more than 8000-fold selectivity for TrkA over TrkB and TrkC. TrkA-IN-3 can be used for the research of pain.

Zurletrectinib is a brain-penetrant, orally active TRK inhibitor (TRKA IC₅₀ = 0.81 nM; TRKB IC₅₀ = 0.145 nM; TRKC IC₅₀ = 0.184 nM). Zurletrectinib exhibits stronger activity as a consequence of its augmented binding affinity for TRK kinases. Zurletrectinib exhibits higher activity against most TRK inhibitor resistance mutations (13 out of 18 mutations). Zurletrectinib can be used for the study of glioma.