cousineg
Messages : 1058
Enregistré le : lun. août 14, 2006 4:36 am
Localisation : Montréal (Ar. Saint-Laurent)

La combinaison Tasigna(nilotinib) + ABL001

sam. oct. 18, 2014 4:36 am

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La combination Tasigna (nilotinib) + ABL001 pourrait réduire l'apparition de la résistance en s'attaquant à deux régions différentes de la protéine BCR/ABL.
Voir ABL001

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sergio
Messages : 1032
Enregistré le : sam. août 12, 2006 7:48 pm

Re: La combinaison Tasigna(nilotinib) + ABL001

sam. oct. 18, 2014 7:04 am

Merci Gilles pour ce suivi.
Les résultats de l'essai clinique seront très intéressants à suivre.
On compte sur toi pour suivre cela.
Grande amitié.
Je suis le président de ALTE-ASSO.
n'hésitez pas à me questionner par mail, par message privé ou par téléphone au 0981377212

cousineg
Messages : 1058
Enregistré le : lun. août 14, 2006 4:36 am
Localisation : Montréal (Ar. Saint-Laurent)

Re: La combinaison Tasigna(nilotinib) + ABL001

mar. déc. 09, 2014 3:15 pm

De la conférence ASH 2014 - San Francisco - décembre 2014

398 ABL001, a Potent Allosteric Inhibitor of BCR-ABL, Prevents Emergence of Resistant Disease When Administered in Combination with Nilotinib in an in Vivo Murine Model of Chronic Myeloid Leukemia
"
Results: In contrast to TKIs that bind to the ATP-site of the ABL1 kinase domain, NMR and X-Ray crystallography studies confirmed that ABL001 binds to a pocket on the BCR-ABL kinase domain that is normally occupied by the myristoylated N-terminus of ABL1. Upon fusion with BCR, this myristoylated N-terminus that serves to autoregulate ABL1 activity is lost. ABL001 functionally mimics the role of the myristoylated N-terminus by occupying its vacant binding site and restores the negative regulation of the kinase activity. Cell proliferation studies demonstrate that ABL001 selectively inhibited the growth of CML and Ph+ ALL cells with potencies ranging from 1-10nM range. In contrast, BCR-ABL-negative cell lines remained unaffected at concentrations 1000-fold higher. With resistance emerging in the clinic to current TKI’s as a result of point mutations in the ATP-site, ABL001 was tested for activity against clinically observed mutations and found to be active in the low nM range. In the KCL-22 mouse xenograft model, ABL001 displayed potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition. The KCL-22 xenograft model was also used to compare the dosing of ABL001 and nilotinib as single agents to dosing a combination of ABL001 and nilotinib. Single agent dosing regimens led to tumor regressions; however, despite continuous dosing, all tumors relapsed within 30-60 days with evidence of point mutations in the resistant tumors. In contrast, animals treated with the combination of ABL001 and nilotinib achieved sustained tumor regression with no evidence of disease relapse either during the 70 days of treatment or for > 150 days after treatment stopped.
Conclusion: ABL001 selectively inhibited the proliferation of cells expressing the BCR-ABL fusion gene and was active against clinically important mutations that arise with current TKI therapy in CML. In an in vivo model of CML, the combination of ABL001 and nilotinib resulted in complete and sustained tumor regression with no evidence of disease relapse. These results provide proof-of-principle that simultaneous targeting of the myristoyl pocket and ATP-pocket by ABL001 and nilotinib, respectively, promotes a more sustained overall efficacy and prevents the emergence of resistance via acquisition of point mutations in the respective binding sites. ABL001 is currently being evaluated in a Phase 1 study in patients with CML and Ph+ ALL."

ChatMalo
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Enregistré le : mar. nov. 29, 2011 6:03 pm
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Re: La combinaison Tasigna(nilotinib) + ABL001

mer. déc. 10, 2014 11:59 am

Merci pour cet extrait. Il y a plein d'autres info intéressantes de ce congrès, et pas seulement en recherche fondamentale !

Cordialement,
Anne, 52 ans
Myélofibrose post Vaquez 2013, Vaquez 2004, Pégasys 135 µg/semaine + aspirine...du sport et des éclats de rire

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