| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T128 |
0-14 |
Sentence |
denotes |
NAK inhibitors |
| T129 |
15-207 |
Sentence |
denotes |
Important virus-associated protein targets include those associated with intracellular membrane trafficking, a cellular process vulnerable to “hijacking” by a broad range of unrelated viruses. |
| T130 |
208-518 |
Sentence |
denotes |
Two host cell kinases that have been found to play an integral role in viral infection and life cycles are members of the numb-associated kinase (NAK) family: (1) AP2-associated protein kinase 1 (AAK1), which promotes endocytosis, and (2) cyclin G–associated kinase (GAK), which mediates endocytosis (39) (40). |
| T131 |
519-816 |
Sentence |
denotes |
AAK1 and GAK are reported to be exploited by a variety of viruses, including HCV and dengue virus, which fall into the same Group IV Baltimore classification as SARS-CoV, MERS-CoV and SARS-CoV-2, and also the Ebola virus, which belongs to a different group (Table 1) (18) (41) (42) (43) (44) (45). |
| T132 |
817-1019 |
Sentence |
denotes |
The importance of AAK1 and GAK for HCV and dengue virus infection in vitro was shown via genetic (siRNA) silencing of AAK1 and GAK, which inhibited viral entry and infectious virus production (42) (46). |
| T133 |
1020-1107 |
Sentence |
denotes |
Genetic (siRNA) silencing of AAK1 and GAK also decreased infection by Ebola virus (46). |
| T134 |
1108-1238 |
Sentence |
denotes |
Several kinase inhibitors have been proposed to exhibit antiviral activity based on their ability to potently target AAK1 and GAK. |
| T135 |
1239-1470 |
Sentence |
denotes |
One drug, the FDA-approved janus kinase (JAK) inhibitor, baricitinib, was identified- in response to the SARS-CoV-2 outbreak- as a possible treatment for COVID-19 by investigators from BenevolentAl and Imperial College London (45). |
| T136 |
1471-1594 |
Sentence |
denotes |
Baricitinib was proposed to potentially reduce infection, based on the drug’s ability to inhibit AAK1 and bind to GAK (45). |
| T137 |
1595-1946 |
Sentence |
denotes |
It has been argued that the therapeutic dosing and low plasma protein binding of baricitinib, in contrast to the JAK kinase inhibitors, ruxolitinib and fedratinib, may make baricitinib more likely to inhibit AAK1 at therapeutically effective and tolerated doses and potentially reduce viral infectivity in patients than the other inhibitors (45) (47). |
| T138 |
1947-2017 |
Sentence |
denotes |
AAK1 and GAK binding potency for these inhibitors is shown in Table 2. |
| T139 |
2018-2026 |
Sentence |
denotes |
Table 2. |
| T140 |
2027-2058 |
Sentence |
denotes |
FDA approved kinase inhibitors: |
| T141 |
2059-2098 |
Sentence |
denotes |
Kinase targets and respiratory benefits |
| T142 |
2099-2324 |
Sentence |
denotes |
Kinase Inhibitor (brand name)(indication; main therapeutic targets) Selected Kinase Target Affinity(antiviral and pulmonary benefit)KINOMEscan(kd<100 nM) Anti-inflammatory activity, cytokine suppression, antifibrotic activity |
| T143 |
2325-2345 |
Sentence |
denotes |
Midostaurin (Rydapt) |
| T144 |
2346-2450 |
Sentence |
denotes |
(acute myeloid leukemia, systemic mastocytosis; multi-targeted; FLT3-ITD, D816V-c-KIT) AAK1, JAK2, JAK3, |
| T145 |
2451-2466 |
Sentence |
denotes |
Kd KIT (220nM), |
| T146 |
2467-2481 |
Sentence |
denotes |
Kd RET (350nM) |
| T147 |
2482-2535 |
Sentence |
denotes |
(48) Anti-inflammatory and cytokine suppression (107) |
| T148 |
2536-2548 |
Sentence |
denotes |
Lestaurtinib |
| T149 |
2549-2682 |
Sentence |
denotes |
(orphan drug status, acute myeloid leukemia; multi-targeted; FLT3, JAK2, TrkA, TrkB, TrkC) AAK1, AXL, FYN, GAK, JAK1, JAK2, JAK3, RET |
| T150 |
2683-2747 |
Sentence |
denotes |
Kd KIT (150nM)* Anti-inflammatory and cytokine suppression (107) |
| T151 |
2748-2770 |
Sentence |
denotes |
Gilteritinib (Xospata) |
| T152 |
2771-2795 |
Sentence |
denotes |
(acute myeloid leukemia; |
| T153 |
2796-2814 |
Sentence |
denotes |
FLT3-ITD; AXL) AXL |
| T154 |
2815-2827 |
Sentence |
denotes |
IC50 (41 nM) |
| T155 |
2828-2834 |
Sentence |
denotes |
(49)** |
| T156 |
2835-2854 |
Sentence |
denotes |
Dasatinib (Sprycel) |
| T157 |
2855-3079 |
Sentence |
denotes |
(chronic myeloid leukemia, Ph+acute lymphoblastic leukemia; multi-targeted; BCR-ABL, SRC) ABL1, ABL2, CSK, FYN, GAK, KIT, LYN, SRC, YES Anti-inflammatory, cytokine suppression, antifibrotic (100) (99) (102) (103) (104) (101) |
| T158 |
3080-3137 |
Sentence |
denotes |
Imatinib Mesylate (Gleevec (US)/Glivec (Europe/Australia) |
| T159 |
3138-3502 |
Sentence |
denotes |
(chronic myeloid leukemia, Ph+acute lymphoblastic leukemia, gastrointestinal stromal tumor, chronic eosinophilic leukemia, hypereosinophilic syndrome, systemic mastocytosis; myelodysplastic syndrome; BCR-ABL, KIT, FIP1L1-PDGFRalpha) ABL1, ABL2, KIT Anti-inflammatory, cytokine suppression/immunomodulatory, antifibrotic (91) (92) (90) (79) (94) (95) (96) (93) (77) |
| T160 |
3503-3522 |
Sentence |
denotes |
Nilotinib (Tasigna) |
| T161 |
3523-3623 |
Sentence |
denotes |
(chronic myeloid leukemia; BCR-ABL) ABL1, ABL2, KIT Antifibrotic ((80) (81) (82) (83) (84) (85) (86) |
| T162 |
3624-3643 |
Sentence |
denotes |
Ponatinib (Iclusig) |
| T163 |
3644-3765 |
Sentence |
denotes |
(chronic myeloid leukemia, Ph+ acute lymphoblastic leukemia; BCR-ABL) ABL1, ABL2, KIT, RET, SRC Cytokine suppression (78) |
| T164 |
3766-3777 |
Sentence |
denotes |
Saracatinib |
| T165 |
3778-3859 |
Sentence |
denotes |
(orphan drug status, idiopathic pulmonary fibrosis; ABL, SRC, LCK, FGR, BLK) ABL1 |
| T166 |
3860-3879 |
Sentence |
denotes |
FYN, LYN, SRC, YES1 |
| T167 |
3880-4003 |
Sentence |
denotes |
IC50 v-ABL (30 nM); IC50 FYN (10 nM); IC50 LYN (5 nM) (isolated protein kinase assay) (186)** Antifibrotic (100) (99) (105) |
| T168 |
4004-4023 |
Sentence |
denotes |
Bosutinib (Bosulif) |
| T169 |
4024-4186 |
Sentence |
denotes |
(chronic myeloid leukemia; ABL, SRC) ABL1, ABL2, AXL, CSK, EGFR, FYN, GAK, LYN, SRC, YES Anti-inflammatory, cytokine suppression, and antifibrotic (104) (87) (88) |
| T170 |
4187-4209 |
Sentence |
denotes |
Baricitinib (Olumiant) |
| T171 |
4210-4261 |
Sentence |
denotes |
(rheumatoid arthritis; JAK1, JAK2) JAK1, JAK2, TYK2 |
| T172 |
4262-4380 |
Sentence |
denotes |
Kd AAK1 (17 nM); Kd GAK (136 nM) (cell-free assay) (47)** Anti-inflammatory and cytokine suppression (106) (107) (108) |
| T173 |
4381-4401 |
Sentence |
denotes |
Ruxolitinib (Jakafi) |
| T174 |
4402-4476 |
Sentence |
denotes |
(myelofibrosis, polycythemia vera; JAK1, JAK2) GAK, JAK1, JAK2, JAK3, TYK2 |
| T175 |
4477-4598 |
Sentence |
denotes |
Kd AAK1 (100 nM); Kd GAK (120 nM) (cell-free assay) (47)** Anti-inflammatory and cytokine suppression, antifibrotic (107) |
| T176 |
4599-4619 |
Sentence |
denotes |
Fedratinib (Inrebic) |
| T177 |
4620-4673 |
Sentence |
denotes |
(myelofibrosis; JAK2) AAK1, ABL1, FYN, GAK, JAK2, SRC |
| T178 |
4674-4781 |
Sentence |
denotes |
Kd AAK1 32 nM; Kd GAK 1 nM (cell-free assay) (47)** Anti-inflammatory and cytokine suppression, (107) (115) |
| T179 |
4782-4806 |
Sentence |
denotes |
Tofacitinib (XELJANZ XR) |
| T180 |
4807-4929 |
Sentence |
denotes |
(ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis; JAK1, JAK3) JAK1, JAK2, JAK3, TYK2 |
| T181 |
4930-5029 |
Sentence |
denotes |
No AAK1 inhibitory activity (47) Anti-inflammatory and cytokine suppression (109) (110) (107) (111) |
| T182 |
5030-5048 |
Sentence |
denotes |
Gefitinib (Iressa) |
| T183 |
5049-5130 |
Sentence |
denotes |
(non-small cell lung cancer; EGFR) EGFR, GAK Antifibrotic (119) (116) (178) (118) |
| T184 |
5131-5150 |
Sentence |
denotes |
Afatinib (Gilotrif) |
| T185 |
5151-5284 |
Sentence |
denotes |
(non-small cell lung cancer, advanced squamous cell carcinoma; Her2/EGFR) EGFR, GAK Anti-inflammatory, antifibrotic (116) (178) (179) |
| T186 |
5285-5314 |
Sentence |
denotes |
Lapatinib (Tykerb and Tyverb) |
| T187 |
5315-5377 |
Sentence |
denotes |
(breast cancer; Erb1/Erb2, EGFR) EGFR Antifibrotic (116) (178) |
| T188 |
5378-5401 |
Sentence |
denotes |
Osimertinib (Tagrisso)’ |
| T189 |
5402-5441 |
Sentence |
denotes |
(non-small cell lung cancer; EGFR) EGFR |
| T190 |
5442-5569 |
Sentence |
denotes |
(60)** AZ5104, active metabolite of osimertinib, downregulates Th17-related cytokine production via inhibition of SRC-ERK-STAT3 |
| T191 |
5570-5575 |
Sentence |
denotes |
(127) |
| T192 |
5576-5595 |
Sentence |
denotes |
Erlotinib (Tarceva) |
| T193 |
5596-5665 |
Sentence |
denotes |
(non-small cell lung cancer, pancreatic cancer; Erb1, EGFR) EGFR, GAK |
| T194 |
5666-5681 |
Sentence |
denotes |
Kd ABL1 (310nM) |
| T195 |
5682-5711 |
Sentence |
denotes |
(48) Antifibrotic (116) (178) |
| T196 |
5712-5731 |
Sentence |
denotes |
Neratinib (Nerlynx) |
| T197 |
5732-5763 |
Sentence |
denotes |
(breast cancer; Her2/EGFR) EGFR |
| T198 |
5764-5784 |
Sentence |
denotes |
Pazopanib (Votrient) |
| T199 |
5785-5926 |
Sentence |
denotes |
(renal cell carcinoma, advanced soft tissue sarcoma; multi-targeted; c-KIT, FGFR, PDGFR, VEGFR) KIT Anti-inflammatory potential, antifibrotic |
| T200 |
5927-5932 |
Sentence |
denotes |
(136) |
| T201 |
5933-5952 |
Sentence |
denotes |
Sorafenib (Nexavar) |
| T202 |
5953-6092 |
Sentence |
denotes |
(renal cell carcinoma, hepatocellular carcinoma, thyroid cancer; multi-targeted; PDGFR, VEGFR, RAF) KIT, RET Antifibrotic (125) (126) (187) |
| T203 |
6093-6118 |
Sentence |
denotes |
Sunitinib malate (Sutent) |
| T204 |
6119-6316 |
Sentence |
denotes |
(renal cell carcinoma, gastrointestinal stromal tumor; multi-targeted; PDGFR, VEGFR) AAK1, AXL, GAK, JAK1, KIT, RET Anti-inflammatory potential, cytokine suppression, antifibrotic (137) (135) (107) |
| T205 |
6317-6334 |
Sentence |
denotes |
Axitinib (Inlyta) |
| T206 |
6335-6460 |
Sentence |
denotes |
(renal cell carcinoma; c-KIT, PDGFR, VEGFR1, VEGFR2, VEGFR3) ABL1, ABL2, KIT Anti-inflammatory and cytokine suppression (128) |
| T207 |
6461-6482 |
Sentence |
denotes |
Vandetanib (Caprelsa) |
| T208 |
6483-6556 |
Sentence |
denotes |
(medullary thyroid carcinoma; EGFR, RET, VEGFR) ABL2, EGFR, GAK, RET, SRC |
| T209 |
6557-6577 |
Sentence |
denotes |
Kd ABL1 (270nM) (48) |
| T210 |
6578-6600 |
Sentence |
denotes |
Regorafenib (Stivarga) |
| T211 |
6601-6717 |
Sentence |
denotes |
(colorectal cancer, gastrointestinal stromal tumor, hepatocellular cancer; PDGFRβ, Raf-1, TIE2, VEGFR1/2/3) KIT, RET |
| T212 |
6718-6739 |
Sentence |
denotes |
Ibrutinib (Imbruvica) |
| T213 |
6740-6920 |
Sentence |
denotes |
(mantel cell lymphoma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, Small lymphocytic lymphoma, marginal zone lymphoma; BTK) EGFR, RET Anti-inflammatory (132) (133) |
| T214 |
6921-6942 |
Sentence |
denotes |
Palbociclib (Ibrance) |
| T215 |
6943-6975 |
Sentence |
denotes |
(breast cancer; CDK4, CDK6) CDK6 |
| T216 |
6976-7012 |
Sentence |
denotes |
Abemaciclib (Verzenio and Verzenios) |
| T217 |
7013-7044 |
Sentence |
denotes |
(breast cancer, CDK4,CDK6) CDK6 |
| T218 |
7045-7061 |
Sentence |
denotes |
IC50 (10 nmol/L) |
| T219 |
7062-7066 |
Sentence |
denotes |
CDK9 |
| T220 |
7067-7083 |
Sentence |
denotes |
IC50 (57 nmol/L) |
| T221 |
7084-7193 |
Sentence |
denotes |
(188)** Abemaciclib in combination with anastrozole led to increased cytokine signaling and immune activation |
| T222 |
7194-7199 |
Sentence |
denotes |
(189) |
| T223 |
7200-7209 |
Sentence |
denotes |
Alvocidib |
| T224 |
7210-7307 |
Sentence |
denotes |
(orphan drug status, acute myeloid leukemia; CDK1, CDK2, CDK4, CDK9) CDK9 Anti-inflammatory (134) |
| T225 |
7308-7327 |
Sentence |
denotes |
Ceritinib (Zykadia) |
| T226 |
7328-7382 |
Sentence |
denotes |
(non-small cell lung cancer; ALK, IGF1R, InsR, STK22D) |
| T227 |
7383-7403 |
Sentence |
denotes |
Crizotinib (Xalkori) |
| T228 |
7404-7452 |
Sentence |
denotes |
(non-small cell lung cancer; ALK/ROS1) ABL1, AXL |
| T229 |
7453-7472 |
Sentence |
denotes |
Masitinib (Masivet) |
| T230 |
7473-7579 |
Sentence |
denotes |
(orphan drug status, potential amyotrophic lateral sclerosis drug; FAK, FGFR3, KIT, LCK, PDGFR) ABL1, KIT, |
| T231 |
7580-7583 |
Sentence |
denotes |
LYN |
| T232 |
7584-7614 |
Sentence |
denotes |
Nintedanib (Ofev and Vargatef) |
| T233 |
7615-7810 |
Sentence |
denotes |
(idiopathic pulmonary fibrosis, non-small cell lung cancer; FGFR, PDGFR, VEGFR) AAK1, ABL1, AXL, JAK2, JAK3, KIT, RET, YES1 Anti-inflammatory, cytokine suppression, antifibrotic (129) (130) (131) |
| T234 |
7811-7823 |
Sentence |
denotes |
Left Column: |
| T235 |
7824-7888 |
Sentence |
denotes |
Drug names and disease indication, and main therapeutic targets. |
| T236 |
7889-7903 |
Sentence |
denotes |
Middle Column: |
| T237 |
7904-8164 |
Sentence |
denotes |
Potency (based on KINOMEscan data) against key proteins associated with respiratory function and proteins involved in viral replication/life span/infection- believed to be necessary for a wide variety of viruses, including SARS-CoV and MERS-CoV and SARS-CoV-2. |
| T238 |
8165-8178 |
Sentence |
denotes |
Right column: |
| T239 |
8179-8280 |
Sentence |
denotes |
Anti-inflammatory activity, cytokine suppression, and antifibrotic activity of the kinase inhibitors. |
| T240 |
8281-8360 |
Sentence |
denotes |
*These values were derived from ChEMBL database: https://www.ebi.ac.uk/chembl/. |
| T241 |
8361-8431 |
Sentence |
denotes |
**These values were not derived from KINOMEscan; References are cited. |
| T242 |
8432-8777 |
Sentence |
denotes |
The multi-targeted kinase inhibitor sunitinib and the EGFR tyrosine kinase inhibitor erlotinib, which potently bind to AAK1 and GAK (dissociation constant [KD] of 11 and 3.1 nM, respectively) (48), were shown to block HCV assembly and inhibit HCV entry with overexpression of AAK1 or GAK effectively reversing their antiviral activity (41) (42). |
| T243 |
8778-8961 |
Sentence |
denotes |
Sunitinib and erlotinib also exhibited broad spectrum activity against dengue, West Nile virus and Zika virus infection in vitro at μM concentrations that were nontoxic to cells (46). |
| T244 |
8962-9148 |
Sentence |
denotes |
To confirm antiviral activity of sunitinib and erlotinib, levels of phospho-AP2, a substrate of AAK1 and GAK, were measured and were found to be reduced in a dose-dependent fashion (46). |
| T245 |
9149-9328 |
Sentence |
denotes |
Genetic (siRNA) depletion of AXL, KIT, and RET, out of a total of 27 protein targets of sunitinib and erlotinib, were found to inhibit dengue infection in a cell-based assay (46). |
| T246 |
9329-9441 |
Sentence |
denotes |
This suggests that these three proteins are potential host targets mediating antiviral effects of the two drugs. |
| T247 |
9442-9627 |
Sentence |
denotes |
Synergy between sunitinib and erlotinib was observed in a murine model of dengue, with 30-60 mg/kg of the drugs administered (doses chosen were at or near the approved human dose) (46). |
| T248 |
9628-9696 |
Sentence |
denotes |
Sunitinib showed some efficacy in this model as a single agent (46). |
| T249 |
9697-9907 |
Sentence |
denotes |
The protective effects of the combination of sunitinib and erlotinib observed in this murine model suggest it is plausible to utilize tolerable drug dosages with the potential to inhibit viral replication (46). |
| T250 |
9908-10084 |
Sentence |
denotes |
It has been suggested, however, that side effects associated with these agents at doses required to inhibit AAK1 may not be tolerated by patients infected with SARS-CoV-2 (45). |
| T251 |
10085-10241 |
Sentence |
denotes |
Gilteritinib is a potent inhibitor of AXL (49), which is one of the targets of sunitinib and erlotinib identified to be important for dengue infection (46). |
| T252 |
10242-10410 |
Sentence |
denotes |
Gilteritinib was reported (unpublished results; preprint) to be one of 24 FDA-approved drugs to show in vitro activity against SARS-CoV-2 (0.1 μM<IC50<10 μM)) (BioRxiv. |
| T253 |
10411-10448 |
Sentence |
denotes |
10.1101/2020.03.20.999730) (Table 1). |
| T254 |
10449-10559 |
Sentence |
denotes |
Gilteritinib has been approved for adult patients with mutant FLT3-positive refractory/relapsed AML (Table 2). |
