PF-114, a selective tyrosine kinase inhibitor (TKI), is active against native and mutated forms of the BCR–ABL oncogene in Philadelphia chromosome (Ph)-positive leukaemias, according to preclinical cellular and in vivo results published in Leukemia.
Martin Ruthardt, from Goethe University in Frankfurt, Germany, and colleagues found that PF-114 was more selective than the second-generation TKIs dasatinib and nilotinib as well as the third-generation TKI ponatinib, which they speculate could reduce the potential for adverse effects.
At a 100 nM concentration, equivalent to an active plasma concentration, PF-114 inhibited at least 90% activity of 11 kinases compared with 47 and 36 kinases suppressed by ponatinib and dasatinib, respectively. Nilotinib blocked only four kinases at this concentration, but extrapolating the data to its clinically relevant concentration of 4 µM resulted in the number of inhibited kinases increasing to 21.
In cell-free assays, PF-114 inhibited not only native ABL kinase but also versions of the enzyme harbouring various clinically relevant mutations, including T315I. The agent also suppressed the proliferation of Ph-positive cell lines derived from patients with chronic myeloid leukaemia (CML) or acute lymphatic leukaemia (ALL).
Additionally, PF-114 was effective against patient-derived long-term cultures, including those responsive and resistant to TKIs as well as one with nonmutational TKI-resistance.
Treatment with PF-114 significantly increased the median survival of mice transplanted with cells expressing the native or T315I mutant form of p185BCR–ABL, inducing a CML-like disease, compared with untreated mice, from 28 days to 39 days and 68 to 132 days, respectively.
Ref : http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2014326a.html