No abstract

Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.

The conductivity of a poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) film can be enhanced by more than two orders of magnitude by adding a compound with two or more polar groups, such as ethylene glycol, meso‐erythritol (1,2,3,4‐tetrahydroxybutane), or 2‐nitroenthanol, to an aqueous solution of PEDOT:PSS. The mechanism for this conductivity enhancement is studied, and a new mechanism proposed. Raman spectroscopy indicates an effect of the liquid additive on the chemical structure of the PEDOT chains, which suggests a conformational change of PEDOT chains in the film. Both coil and linear conformations or an expanded‐coil conformation of the PEDOT chains may be present in the untreated PEDOT:PSS film, and the linear or expanded‐coil conformations may become dominant in the treated PEDOT:PSS film. This conformational change results in the enhancement of charge‐carrier mobility in the film and leads to an enhanced conductivity. The high‐conductivity PEDOT:PSS film is ideal as an electrode for polymer optoelectronic devices. Polymer light‐emitting diodes and photovoltaic cells fabricated using such high‐conductivity PEDOT:PSS films as the anode exhibit a high performance, close to that obtained using indium tin oxide as the anode.

The external electroluminescence (EL) quantum efficiency (QE EL ) of a polymer light-emitting diode (PLED) can be affected by the following four factors: a) charge balance, b) the efficiency of producing singlet excitons, c) photoluminescence quantum efficiency (QE PL ), and d) the output coupling effect.[1] The QE PL can approach unity and the efficiency of producing singlet excitons can be high in long-chain polymers. [2,3] Therefore, the dominating factor for achieving high efficiency for a given polymer is the balance and confinement of electrons and holes. Unfortunately, most conjugated polymers have unbalanced charge-transport properties as the hole mobility is much larger than the electron mobility. In this manuscript, we report a general method to significantly increase the efficiency of PLEDs by controlling the charge injection and distribution through material processing and interface engineering in the device. By blending high-bandgap and low-bandgap polymers in proper ratios, we were able to introduce charge traps in the light-emitting polymer (LEP) layer. Similarly, by introducing an electron-injection/hole-blocking layer, we were able to enhance the minority carrier (electron) injection and confine holes to the emissive layer. Efficient and balanced charge injection, as well as charge confinement, are attained simultaneously, and as a result high-efficiency devices can be achieved. This is a simple yet powerful concept in enhancing the overall efficiency of PLEDs. To illustrated our concept, we have blended 0.25-2 % of poly[2-methoxy-5-(2′-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV) with poly(9,9-dioctylfluorene) (PFO) as the active polymer layer for PLEDs. A Cs 2 CO 3 electron-injection (and hole-blocking) layer is used at the cathode interface. The emission from the device covers colors from white to yellow, depending on the blend ratio, with the highest peak efficiency being 16 lm W -1 . To the best of our knowledge, this is the highest reported efficiency for a white-light emitting PLED.There are several benefits to using a polymer blend: 1) the low-bandgap LEP behaves as a dopant for energy transfer from the higher-bandgap LEP, 2) the low-bandgap LEP behaves as a charge-trapping site to trap (and confine) the injected charges, which is particularly important in the low-voltage regime where only one type of charge is often present, and 3) the trapped electrons in the low-bandgap LEP will eventually help with the injection of holes and lead to self-balanced charge injection. When this LEP blend system is coupled with an electron-injection (and hole-blocking) layer of Ca(acac) 2[4] (acac: acetylacetonate) or Cs 2 CO 3 [5] at the cathode interface, holes are blocked within the LEP layer as well. As a result, both electrons and holes are effectively confined in the LEP layer rather than being extracted directly at the electrodes. Hence, efficient recombination occurs due to the overlapping distribution of electrons and holes (through formation of excitons). All of these factors can help to i...