PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation

Abstract

Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

An Imatinib–non‐responsive patient with an ABL Leu387Trp mutation achieves cytogenetic and molecular response under bosutinib: Case report and biological characterization

“…Next, we evaluated the effects of other tyrosine kinase inhibitors (bosutinib, dasatinib, nilotinib, ponatinib, and PF‐114) on the Ba/F3_BCR/ABL1_ Leu387Trp cell line. Interestingly, the mutated cell line showed a moderate resistance to dasatinib and nilotinib, with ~2.4‐fold and ~3.8‐fold increase resistance compared to the WT, respectively.…”

PF-114, a Novel Inhibitor of Bcr-Abl Chimeric Tyrosine Kinase, Attenuates Intracellular CrkL Phosphorylation and Kills Chronic Myeloid Leukemia Cells

“…Недавно разработанный нами ингибитор Bcr-Abl третьего поколения PF-114 (рис. 2) в доклинических исследованиях показал эф-фективность при ХМЛ с мутацией T315I и существенно более селективное ингибирование протеинкиназ, а также безопасность [12]. В настоящей работе исследованы важные свойства PF-114 как прототипа лекарственного препарата: ци-тотоксичность для Bcr-Abl-позитивных и -негативных клеток, а также ингибирование киназной активности Bcr-Abl в линии клеток ХМЛ по снижению фосфорили-рования белка CrkL.…”

“…Важно, что высокая специфичность к внутриклеточной мишени, преимущественная цитотоксич-ность для клеток ХМЛ, способность подавлять функцию химерной тирозинкиназы как результат клинически важной мутации, а также благоприятные фармакологические свойства [12] обусловливают перспективность нового пре-парата для лечения ХМЛ на основе соединения PF-114.…”

BCR: a new target in resistance mediated by BCR/ABL-315I?

“…The constitutive activation of the ABL-kinase activity induces aberrant proliferation and neoplastic transformation by constitutive activation of down-stream signaling pathways such as RAS, PI3 kinase, or STATs [ 1 , 2 ]. Several animal models proved that BCR/ABL is responsible for the induction of the leukemic phenotype related to the t(9;22) [ 3 - 6 ].…”

“…The only approved exception is the multi-targeted kinase inhibitor ponatinib [ 19 - 21 ]. Other TKIs, such as PF-114, able to target BCR/ABL harboring the T315I are actually in pre-clinical development [ 6 ].…”