PF‑114, a novel selective inhibitor of BCR‑ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells

Abstract

A t(9;22) chromosomal translocation which forms the chimeric tyrosine kinase breakpoint cluster region (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL) is a key mechanism underlying the pathogenesis of chronic myelogenous leukemia (CML). Pharmacological inhibition of BCR-ABL with imatinib (Gleevec) has been reported as an effective targeted therapy; however, mutations (including the kinase domain of ABL) suppress the efficacy of inhibitors. PF-114, a derivative of the third generation BCR-ABL inhibitor ponatinib, demonstrated a high inhibitory activity against wild-type and mutant BCR-ABL forms, such as the clinically important T315I. Furthermore, PF-114 exhibited preferential kinase selectivity, safety, notable pharmacokinetic properties and therapeutic efficacy in a murine model. Investigation into the mechanisms of CML cell death revealed an exceptional potency of PF-114 (at low nanomolar concentrations) for the CML-derived K562 cell line, whereas leukemia cell lines that lack the chimeric tyrosine kinase were markedly more refractory. The molecular ordering of events mechanistically associated with K562 cell death included the dephosphorylation of CrkL adaptor protein followed by inhibition of ERK1/2 and Akt, G1 arrest, a decrease of phosphorylated Bcl-2-associated death promoter, Bcl-2-like protein 11, BH3 interacting-domain death agonist, Bcl-extra large and Bcl-2 family apoptosis regulator, and reduced mitochondrial transmembrane potential. Increased Annexin V reactivity, activation of caspases and poly(ADP-ribose) polymerase cleavage were proposed to lead to internucleosomal DNA fragmentation. Thus, PF-114 may be a potent inducer of apoptosis in CML cells. Nevertheless, activation of STAT3 phosphorylation in response to PF-114 may permit cell rescue; thus, a combination of BCR-ABL and STAT3 inhibitors should be considered for improved therapeutic outcome. Collectively, the targeted killing of BCR-ABL-positive cells, along with other beneficial properties, such as in vivo characteristics, suggests PF-114 as a potential candidate for analysis in clinical trials with CML patients.

Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst

“…Next, activation of caspase 3 was determined by neither by immunoblotting ( Figure 3 G) nor immunostaining ( Figure S2 ). No proteolytic processing of poly(ADPribose)polymerase (PARP) was observed upon cell exposure to CuO + NAC, whereas the reference compounds Dox or PF-114, a Bcr-Abl inhibitor [ 28 ], induced cleavage of PARP and caspase 3 in K562 cells ( Figure 3 G and Figure S2 ). Altogether, we interpreted the complex mode of cell death by CuO + NAC as a caspase-independent apoptosis coupled with an early necrosis.…”

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

“…Other new molecules are already under clinical trials e.g., PF-114, HQP1351 (Olverembatinib), and K0706 (Vodobatinib), which function competitively as inhibitors of BCR-ABL1 TK at the ATP-binding site ( Table 2 ) [ 249 ]. These inhibitors have presented an increased potency against a wide range of BCR-ABL1 mutations [ 249 , 250 , 251 , 252 ] and may overcome some the limitations of approved TKIs. Unlike other TKIs, Olverembatinib is able to bind to the kinase in the presence of T315I mutations since it does not form the hydrogen bond with the hydroxyl group at this residue [ 251 ].…”

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

“…Here, we have demonstrated that the characteristic oncogene CRKL is the downstream effector of Hh‐GLI2 pathway, providing CRKL as a putative drug target for Hh‐related NSCLC. As a matter of fact, CRKL inhibitor PF‐114 has recently reported to induce tumour cell apoptosis 24 . Given that our studies only uncover CRKL is a critical transcriptional target of Hh‐GLI2 pathway in NSCLC cells, it will be interesting to test whether this transcriptional regulation also exists in other types of cancer.…”