Table 4.
Potential inhibitors and drugs for hypoxia induced TNBC.
| S. No. | Inhibitors/Drugs | Mechanism of Action | References |
|---|---|---|---|
| A. | Tropomycin receptor kinase (TRK) Inhibitors | (203, 215) | |
| 1. | Larotrectinib | Binds to Trk and prevent neurotrophin-Trk interaction and Trk activation | |
| 2. | Selitrectinib | Inhibitor of Trk receptors | |
| 3. | Repotrectinib | Inhibitor of Trk receptors | |
| B. | Human epidermal growth factor receptor (HER) Inhibitors | (203, 215) | |
| 1. | Netatinib | Inhibit Growth factor receptors | |
| C. | Phosphoinositide 3-kinase (PI3K) Inhibitors | (203, 215) | |
| 1. | Alpelisib | Inhibit class I PI3K p110α | |
| 2. | Taselisib | PI3K Inhibitor targeting PI3Kα/δ/γ | |
| 3. | Buparlisib | Inhibits class I PIK3 in ATP-competitive manner | |
| 4. | Sapanisertib | Inhibitor of raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2) | |
| 5. | Ipatasertib | Inhibit PI3K pathway | |
| 6. | Uprosertib | Binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway | |
| 7. | Samotolisib | Inhibitor of certain class I phosphoinositide 3-kinase (PI3K) isoforms and mammalian target of rapamycin kinase (mTOR) in the PI3K/mTOR signaling pathway | |
| 8. | Copanlisib | Inhibit PI3K-α and PI3K-δ isoforms | |
| 9. | Eganelisib | Inhibits gamma isoform of phosphoinositide-3 kinase | |
| 10. | Gedatolisib | Inhibits both PI3K and mTOR kinases | |
| 11. | GDC-0941 | Inhibit PI3K pathway | |
| 12. | NVP-BKM120 (BKM-120) | Inhibit PI3K pathway | |
| 13. | BEZ235 (NVP-BEZ235) |
Inhibit PI3K/mTOR pathway | |
| 14. | GDC-0980 | Inhibit PI3K/mTOR pathway | |
| D. | Protein kinase B (PKB/AKT) Inhibitors | (203, 215) | |
| 1. | Ipatasertib | Inhibits AKT pathway | |
| 2. | Capivasertib | Inhibits AKT pathway | |
| E. | Mammalian target of rapamycin (mTOR) Inhibitors | (203, 215) | |
| 1. | Everolimus | Inhibits mTOR | |
| 2. | Vistusertib | Inhibits mTOR 1/mTOR2 | |
| 3. | Gedatolisib | PI3K/mTOR inhibitor | |
| F. | Mitogen-activated protein kinase (MEK) Inhibitors | (203, 215) | |
| 1. | Trametinib | Inhibits MEK pathway | |
| 2. | Binimetinib | Inhibits MEK pathway | |
| 3. | Selumetinib | MEK 1/2 inhibitor | |
| G. | Cyclin-dependent kinase 4 and 6 (CDK4/6) Inhibitors | (22, 203, 215) | |
| 1. | Palbociclib | Inhibits CDK4/6 | |
| 2. | Abemaciclib | Inhibits CDK4/6; G0/G1 arrestor, induce chromatin condensation | |
| 3. | Ribociclib | Inhibits CDK4/6; G0/G1 arrestor, induce apoptosis | |
| H. | Checkpoint kinase 1 (CHK1) Inhibitors | (22, 203, 215) | |
| 1. | LY2880070 | Inhibits CHK 1 | |
| 2. | Prexasertib | Inhibits CHK 1 and induced Homologous recombination deficiency | |
| I. | WEE1 Inhibitors | (22, 203, 215) | |
| 1. | AZD1175 | Inhibits WEE1 | |
| 2. | ZN-c3 | Inhibits WEE2 | |
| 3. | MK1775 | Inhibits WEE 1 kinase, G2/M arrestor; sensitize cells to cisplatin | |
| J. | Checkpoint kinase 2 (CHK2) Inhibitors | (203, 215) | |
| 1. | LY2606368 | Inhibits CHK2 | |
| K. | Androgen Receptors (AR) Inhibitors | (22, 306, 307) | |
| 1. | Bicalutamide | Inhibits AR | |
| 2. | Enzalutamide | Inhibits AR | |
| 3. | Abiraterone | Inhibits AR | |
| 4. | Enobosarm | Inhibits AR | |
| 5. | Darolutamide | Inhibits AR | |
| 6. | 17-DMAG | HSP-90 inhibitor, regulate the stability of AR | |
| 7. | VT464 | Involved in synthesis of AR | |
| L. | Atxia telangiectasia and Rad3-related (ATR) Inhibitors | (203, 215) | |
| 1. | Ceralasertib | Inhibits ATR | |
| M. | RAD51 Inhibitor | (203, 215) | |
| 1. | CYT-0851 | Inhibits RAD51 | |
| N. | Poly (ADP ribose) polymerase (127) Inhibitors | (22, 203, 215) | |
| 1. | Olaparib | Inhibit PARP | |
| 2. | Talazoparib | Inhibit PARP | |
| 3. | Veliparib | Inhibit PARP | |
| 4. | Rucaparib | Inhibit PARP | |
| 5. | Niraparib | Inhibit PARP | |
| 6. | Pamiparib | Inhibit PARP | |
| 7. | Fluzoparib | Inhibit PARP | |
| 8. | Iniparib | Inhibit PARP1 | |
| O. | Carbonic anhydrase IX (CAIX) Inhibitors | (308) | |
| 1. | SLC-0111 | Inhibitor of carbonic anhydrases IX/XII; resulted in CSCs and EMT inhibition in TNBC cell lines | |
| 2. | DTP348 | CAIX inhibitor/radiosensitizer, inhibits HIF-1α in TNBC by targeting Hsp 90 | |
| P. | Cell cycle Inhibitors | (203, 215) | |
| 1. | Trilaciclib | Inhibits CDK4/6; G)/G1 arrestor | |
| 2. | Etoposide | Inhibits CDK4/6; G)/G1 arrestor | |
| 3. | PF-06873600 | Inhibitor of CDK4/6 | |
| 4. | Abemaciclib (Verginio) | Inhibitor of CDK4/7 | |
| 5. | Prexasertib | Inhibits CHK 1 and induced Homologous recombination deficiency | |
| Q. | Vascular endothelial growth factor/receptor (VEGF/VEGFR) Inhibitors | (203, 215) | |
| 1. | Anlotinib | Inhibitors of VEGFR 1/2 and FGFR 1/4 | |
| 2. | Apatinib | Inhibitors of VEGFR 2 | |
| 3. | Afatinib | Inhibitors of ErbB family of receptors (EGFR/ErbB1, HER2/ErbB2, ErbB3, and ErbB4) | |
| 4. | Lenvatinib | Inhibitors of FGFR 3 and decreases the phosphorylation of downstream molecules of the FGF signaling pathway (such as FRS2, Erk, and p38 MAPK), and induced PARP cleavage | |
| 5. | Erlotinib | Reduces VEGF promoter activity | |
| 6. | Famitinib | inhibitor of targeting VEGFR2, PDGFR and c-kit | |
| 7. | Pyrotinib | Irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets hEGFR (HER) 1, HER2, and HER4 | |
| 8. | Bevacizumab | Inhibitors of VEGFR 2 | |
| R. | Epidermal growth factor receptor (EGFR) Inhibitors | (22, 203, 215) | |
| 1. | Dasatinib | Block BCSCs enrichment and Src activation | |
| 2. | Gefitinib | Inhibits AKT and MEK pathway | |
| 3. | Sorafenib | Modulates the SHP-1/STAT3 axi | |
| 4. | Nimotuzumab | Inhibitor of EGFR pathway and has low immunogenicity | |
| 5. | Panitumumab | Inhibitor of EGFR pathway | |
| 6. | SCT200 | Inhibitor of EGFR pathway | |
| S. | g-Secretase Inhibitors | (215) | |
| 1. | AL101 | Inhibitor of NOTCH 1, 2, 3, and 4 | |
| 2. | PF-03084014 | Inhibitor of g-secretase inhibitor | |
| T. | AXL Kinase Inhibitors | (215) | |
| 1. | Bemcentinib | AXL kinase inhibitor; inhibits Axl phosphorylation | |
| U | Hedgehog pathway Inhibitors | (215) | |
| 1. | Vismodegib | Hedgehog (Hh) pathway inhibitor | |
| V. | CXCL8 and CXCR1/2 Inhibitors | (203, 215) | |
| 1. | Reparixin | Allosteric inhibitor of CXCR1, reduced the CSC content of human BC | |
| W. | Hypoxia-activated prodrugs (HAP) of DNA-damaging cytotoxins | ||
| a. | DNA breakers | (309) | |
| 1. | Tirapazamine | Produces hydroxyl or and benzotriazinyl radicals as the DNA damaging reactive species in hypoxic cells | |
| 2. | SN30000 | Selective activation to a DNA-reactive radical species under hypoxia | |
| b. | DNA alkylators | (309) | |
| 1. | TH-302 | Cellular reductases that generate a radical anion through 1-electron reduction | |
| 2. | PR-104 | Exploit hypoxia and HR defects in tumors, with translational implications for TNBC and other HR-deficient malignancies | |
| 3. | SN30548 | Exploit hypoxia and HR defects in tumors, with translational implications for TNBC and other HR-deficient malignancies | |