| Description | In September 2012, the US FDA approved bosutinib (also referred to as
SKI-607) for the treatment of relapsed or refractory chronicmyeloid leukemia
(CML) for patients with resistance or intolerance to prior therapy. The
National Cancer Institute estimates that in 2012, 5430 men and women were
diagnosed with CML and 610 died of CML. First and second-line therapies
for the treatment of CML include imatinib, dasatinib, and nilotinib.
Bosutinib, which was initially identified as a Src inhibitor, was later found to be a dual inhibitor of Bcr–Abl (IC50=1.4 nM) and Src family kinases (IC50=3.5 nM). Bosutinib inhibits 16 of 18 imatinib-resistant forms of
Bcr–Abl expressed in murine myeloid cell lines. In preclinical in vivo studies, bosutinib at 15 mg/kg administered orally for 5 days caused regression of K562 CML tumors in nude mice and in BaF3 tumors expressing wild type or different imatinib-resistant Bcr–Abl mutants at varying doses.
A manufacturing process for the synthesis of bosutinib monohydrate has been
reported that employs a key three-component cyclization reaction involving
an aniline, a cyanoacetamide intermediate, and triethyl orthoformate followed by cyclization using phosphorous oxytrichloride and an optimized hydration procedure. |
| Chemical Properties | Pale Yellow Solid |
| Originator | Wyeth (United States) |
| Uses | A novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. |
| Uses | peripheral vasolidator increases cerebral blood flow, potential therapeutic for Altzheimer’s disease, cognitive impairment and dementia |
| Uses | Bosutinib (SKI-606) is a novel, dual Src/Abl inhibitor with IC50 of 1.2 nM and 1 nM, respectively. |
| Definition | ChEBI: An aminoquinoline that is 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline bearing additional cyano and methoxy substituents at positions 3 and 6 respectively. |
| Brand name | Bosulif |
| General Description | Bosutinib is a safe oral medicine with good bioavailability. It is effective for treating chronic myeloid leukemia (CML). It is also a potent ATP-competitive inhibitor for Src tyrosine kinase. Bosutinib inhibits epidermal growth factor receptor (EGFR). It suppresses solid tumors associated with breast, pancreas and prostate. |
| Biochem/physiol Actions | Bosutinib (SKI-606) is an orally active; dual Src/Abl tyrosine kinase inhibitor with potent antiproliferative activity. It does not appear to inhibit c-Kit and PDGRF, which are thought to be the cause of numerous side effects in anticancer treatment with some other tyrosine kinase inhibitors. |
| Clinical Use | Protein kinase inhibitor:
Treatment of Philadelphia chromosome-positive
chronic myelogenous leukaemia resistant or
intolerant to prior therapy |
| Drug interactions | Potentially hazardous interactions with other drugs
Analgesics: possibly increased risk of ventricular
arrhythmias with methadone.
Anti-arrhythmics: possibly increased risk of ventricular
arrhythmias with amiodarone and disopyramide;
concentration possibly increased by dronedarone -
avoid or consider reducing dose of bosutinib.
Antibacterials: concentration possibly increased
by ciprofloxacin, clarithromycin, erythromycin and
telithromycin - avoid or consider reducing dose
of bosutinib; possibly increased risk of ventricular
arrhythmias with moxifloxacin; concentration
reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Antifungals: concentration increased by ketoconazole
and possibly by fluconazole, itraconazole,
posaconazole and voriconazole - avoid or consider
reducing dose of bosutinib.
Antimalarials: possibly increased risk of
ventricular arrhythmias with chloroquine and
hydroxychloroquine.
Antipsychotics: possibly increased risk of ventricular
arrhythmias with haloperidol; avoid with clozapine,
increased risk of agranulocytosis.
Antivirals: concentration possibly increased by
atazanavir, boceprevir, darunavir, fosamprenavir,
indinavir, ritonavir, saquinavir and telaprevir - avoid
or consider reducing dose of bosutinib; concentration
possibly reduced by efavirenz and etravirine - avoid.
Aprepitant: concentration possibly increased - avoid
or consider reducing dose of bosutinib.
Beta-blockers: possibly increased risk of ventricular
arrhythmias with sotalol.
Bosentan: concentration of bosutinib possibly
reduced - avoid.
Calcium channel blockers: concentration possibly
increased by diltiazem or verapamil - avoid or
consider reducing dose of bosutinib.
Cytotoxics: concentration possibly increased by
imatinib - avoid or consider reducing dose of bosutinib.
Domperidone: avoid concomitant use, risk of
ventricular arrhythmias.
Fosaprepitant: concentration possibly increased by
fosaprepitant - avoid or consider reducing dose of
bosutinib
Grapefruit juice: concentration possibly increased by
grapefruit juice - avoid or consider reducing dose of
bosutinib.
Modafinil: concentration of bosutinib possibly
reduced - avoid. |
| Metabolism | Mainly hepatically metabolised. The major circulating
metabolites identified in plasma are oxydechlorinated
(M2) bosutinib (19% of parent exposure) and
N-desmethylated (M5) bosutinib (25% of parent
exposure), with bosutinib N-oxide (M6) as a minor
circulating metabolite. All the metabolites are inactive.
Excretion is mainly via the faeces. |
| References | Golas et al. (2003), SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice; Cancer Res., 63 375
Remsing Rix et al. (2009), Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells; Leukemia, 23 477
Redaelli et al. (2009), Activity of bosutinib, Dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants; J. Clin. Oncol., 27 469
MacDonald et al. (2018), Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells; Leuk. Lymphoma, 59 2941
Vultur et al. (2008), SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells; Mol. Cancer Ther., 7 1185 |
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