Table 1.
List of drugs of breast cancer brain metastasis that were repositioned and their BBB permeability
| Drug target | Drug name | Approval status |
Approved indications | "Rule of Five" for CNS drugsa |
BBB permeability |
|---|---|---|---|---|---|
| HDAC1, HDAC2 | Vorinostat | Approved | Cutaneous T-cell lymphoma | ✓ | 2009, Clin Can Res (26) |
| KDR, RET | Sunitinib | Approved | Gastrointestinal stromal tumor (GIST); advanced renal cell carcinoma (RCC); advanced pancreatic neuroendocrine tumors (pNET) | ✓ | 2009, Lancet Oncol (45) |
| KDR | Cabozantinib(XL184) | Phase II/III | Breast cancer (phase II); metastatic prostate cancer (phase II); carcinoid tumor (phase II); pancreatic neuroendocrine tumor (phase II); thyroid cancer (phase III); glioblastoma multiforme (phase II); carcinoma, non-small cell lung (phase II); astrocytic tumors (phase II) | ✓ | 2011, J Clin Oncol (28) |
| RET | Imatinib | Approved | Chronic myeloid leukemia (CML) | ✓ | |
| RAF1, KDR | Sorafenib | Approved | Hepatocellular carcinoma; renal cell carcinoma | ✓ | |
| Pazopanib | Approved | Renal cell carcinoma | ✓ | 2010, Clin Can Res (27) | |
| FYN | Dasatinib | Approved | Chronic myeloid leukemia (CML); Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) | ✓ | 2008, Blood (44) |
| NFKB1 | Dexamethasone | Approved | Allergic states; dermatologic diseases; endocrine disorders; gastrointestinal diseases; hematologic disorders; neoplastic diseases; nervous system; ophthalmic diseases; renal diseases; respiratory diseases; rheumatic disorders | ✓ | |
| Thalidomide | Approved | Multiple myeloma; erythema nodosum leprosum | ✓ | ||
| Pranlukast | Phase III | Chronic sinusitis | ✓ | ||
| GRB2 | Pegademase | Approved | Adenosine deaminase (ADA) deficiency | ||
| IKBKB | Auranofin | Approved | Rheumatoid arthritis | ||
| Arsenite | Not approved | ||||
| VIM | Acetate ion | Not approved | |||
| PHGDH | NADH | Not approved |
a
The "Rule of Five" is so named because all the essential physical properties of compounds are parameters of five. According to this rule, a good absorption and permeability are likely if: molecular weight is ≤500; oil/water distribution coefficient (LogP) is ≤5; hydrogen bond donors ≤5 (expressed as the sum of OHs and NHs); hydrogen bond acceptor ≤10 (expressed as the sum of Ns and Os); and number of rotatable bonds ≤10.