Table 2.
Target Specificity and IC50 of NTRK-Targeting Inhibitors
| IC50 (nM) | |||||
|---|---|---|---|---|---|
| Drug Name (company) | NTRK1 | NTRK2 | NTRK3 | Other Targets (IC50 < 500 nM | Reference |
| FDA-approved drugs | |||||
| Cabozantinib (XL-184; Exelixis) | NA | 7 | NA | ALK, AXL, BLK, BTK, EPHA4, EPHB4, FAK, FLT1, FLT3, FLT4, FYN, KDR, KIT, LYN, MAP2K1, MET, PDGFRB, RAF1, RET, RON, SAPK4, TIE2, YES |
US Food and Drug Administration35 |
| Crizotinib (PF-02341066; Pfizer) | 1 | 1 | NA | ABL, ALK, ARG, AXL, FES, LCK, LYN, MER, MET, RON, ROS1, SKY, TIE2, YES |
US Food and Drug Administration36 |
| Midostaurin (PKC-412; Novartis) | 11 | 51 | 15 | AURKA, BRSK1, CSF1R, FLT3, MAP3K9, PDGFRA, PDGFRB, PHKG1, PKN1, PRKCA, PRKCB2, RPS6KA1, RPS6KA2, RPS6KA3, STK4, SYK, TBK1 |
US Food and Drug Administration37 |
| Nintedanib (BIBF-1120; Boehringer Ingelheim) |
17.1 | 263.9 | 142.5 | FGFR, FLT3, LCK, LYN, PDGFR, SRC, VEGFR |
Nishiyama et al,38 Hilberg et al39 |
| Regorafenib (BAY 73–4506; Bayer/ Onyx) |
74 | NA | NA | ABL, DDR2, EPHA2, FGFR1, FGFR2, FLT1, FLT3, HCK, KDR, KIT, LYN, MER, PDGFRA, PTK5, RAF1, RET, SAPK2A, SAPK2B, TIE2 |
US Food and Drug Administration40 |
| Drugs in development(ongoing clinical trials) | |||||
| Altiratinib (Deciphera Pharmaceuticals) |
0.9 | 4.6 | 0.8 | MET, TIE2 VEGFR2 | Smith et al41 |
| Belizatinib (TSR-011; Tesaro) | < 3 | < 3 | < 3 | ALK | Weiss et al42 |
| BMS-754807 (Bristol-Myers Squibb) |
7 | 4 | NA | AURKA, AURKB, FLT3, IGF1R, INSR, MET, RON |
Carboni et al43 |
| BMS-777607 (Bristol-Myers Squibb) |
290 | 190 | NA | AURKB, AXL, FLT3, KDR, LCK, MER, MET, RON, TYRO3 |
Schroeder et al44 |
| Danusertib (Nerviano) | 31 | NA | NA | ABL, AURKA, AURKB, AURKC, FGFR1, RET |
Carpinelli et al45 |
| DS-6051b (Daiichi Sankyo) | <2 | <2 | <2 | ALK, ROS1 | Kiga et al46 |
| ENMD-2076 (CASI) | 24 | NA | NA | ABL1, AURKA, AURKB, BLK, CSF1R, FAK, FGFR1, FGFR2, FLT3, FLT4, FYN, JAK2, KDR, KIT, LCK, PDGFRA, RET, SRC, YES1 |
Fletcher et al47 |
| Entrectinib (RXDX-101; Ignyta/ Nerviano) |
2 | 0.1 | 0.1 | ALK, ROS1 | Braud et al,48 Rolfo et al49 |
| Larotrectinib (LOXO-101; Loxo Oncology) |
9 | 4 | 4 | — | Drilon et al,50 Ghilardi et al51 |
| Lestaurtinib (CEP-701; Cephalon/ Kyowa) |
25 | 25 | 25 | FLT3, JAK2 | Shabbir et al,52 Miknyoczki et al53 |
| LOXO-195 (Loxo Oncology) | 4 | 2 | 1 | — | Drilon et al50 |
| Merestinib (LY2801653; Eli Lilly) | 15–320 | 15–320 | 15–320 | AXL, DDR1, DDR2, FLT3, MET, MERTK, MKNK1, MKNK2, MST1R, ROS1, TEK |
Yan et al,54 Konicek et al55 |
| MK-5108 (Merck/Vertex) | 2 | 13 | NA | ABL, AURKA, AURKB, AURKC, AXL, BRK, EPHA1, EPHA2, FLT1, FLT4, GSK3A, JNK3, KDR, LOK, MER, PTK5, ROS, TIE2, YES |
Shimomura et al56 |
| Milciclib (PHA-848125; Nerviano /Tiziana) |
53 | NA | NA | CDK1/cyclin B, CDK2/cyclin CDK2/cyclin E, CDK4/cyclin D1, CDK5/p3 CDK7/cyclin H |
Brasca et al57 |
| PLX-7486 (Plexxikon) | < 10 | < 10 | < 10 | AURKA, AURKB, CSF1R, MAP3K2, MAP3K3 | ECMC Network58 |
| Sitravatinib (MGCD516; Mirati Therapeutics) | 5 | 9 | NA | RET, CBL, CHR4q12, DDR, AXL, DDR1, DDR2, EPHA2, EPHA3, EPHA4, EPHB2, EPHB4, FLT1, FLT3, FLT4, KDR, KIT, MER, MET, PDGFRA, RET, RON, ROS, SRC |
Patwardhan et al59 |
| Preclinical drugs | |||||
| ANA-12 | NA | 10 | NA | — | Ivanov et al60 |
| AZD-7451 (AstraZeneca) | 0.2 | < 3 | < 3 | — | Cazorla et al62 |
| Cyclotraxin B (Tocris Biosciences) | NA | 0.3 | NA | — | Cazorla et al61 |
| Dovitinib (TKI-258; Novartis) | 69 | NA | NA | CSF1R, FGFR1, FGFR3, FLT1, FLT3, FLT4, KDR, KIT, PDGFRB |
Chong et al63 |
| Foretinib (formerly GSK-1363089/ XL880; GlaxoSmithKline/ Exelixis) |
34.8 | 118.2 | 258.2 | FLT1, FLT4, FLT3, KDR, KIT, MET, PDGFRA, PDGFRB, RON, TIE2, VGFR |
Nishiyama et al,38 Qian et al64 |
| GNF-5837 (GNF) | 8 | 12 | 7 | KIT, PDGFR | Albaugh et al65 |
| GW-441756 (Tocris Biosciences) | 2 | NA | NA | — | Wood et al66 |
| PF-03814735 (Pfizer) | 30 | NA | NA | AURKA, AURKB, FAK, FLT1 | Jani et al67 |
| PF-06273340 (Pfizer) | 6 | 4 | 3 | — | Skerratt et al68 |
| RXDX-102 (Ignyta/Nerviano) | < 5 | < 5 | < 5 | — | Ignyta69 |
| SNS-314 (Sunesis) | 12 | 5 | NA | AURKA, AURKB, AURKC, AXL, CSFIR, DDR2, FLT4, RAF1 |
Gamo et al70 |
Abbreviations: FDA, US Food and Drug Administration; GNF, Genomics Institute of the Novartis Research Foundation; IC50, half-maximal inhibitory concentration; NA, not applicable; NDA, new drug application; NTRK, neurotrophic-tropomyosin receptor tyrosine kinase.