In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.

In this paper, an asymmetric plasmonic structure composed of a MIM (metal-insulator-metal) waveguide and a rectangular cavity is reported, which can support double Fano resonances originating from two different mechanisms. One of Fano resonance originates from the interference between a horizontal and a vertical resonance in the rectangular cavity. And the other is induced by the asymmetry of the plasmonic structure. Just because the double Fano resonances originate from two different mechanisms, each Fano resonance can be well tuned independently by changing the parameters of the rectangular cavity. And during the tuning process, the FOMs (figure of merit) of both the Fano resonances can keep unchanged almost with large values, both larger than 650. Such, the transmission spectra of the plasmonic structure can be well modulated to form transmission window with the position and the full width at half maximum (FWHM) can be tuned freely, which is useful for the applications in sensors, nonlinear and slow-light devices.

Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (K(d)) and enzyme inhibition (IC(50)) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.

As fundamental elements, optical diodes are required for on-chip optical communications and computing. However, it is still a challenge to realize ultracompact devices working in the terahertz (THz) range. Here an optical diode device with a bandwidth up to 100 GHz that is able to produce a highly asymmetric THz propagation was designed by coupling a gradient metasurface and subwavelength waveguide modes. This system is based on the breaking of the momentum symmetry at the interface with phase discontinuities. The asymmetric transmission process generated by THz mode conversion is detected by employing time-resolved phase contrast imaging. The results agree well with full-wave electromagnetic simulations. Moreover, the performance of the working bandwidth and the ratio of transmission of the device can be optimized by the induced arbitrary scattering phase. These performances indicate that this design provides a very effective method and a versatile platform for on-chip information processing by preventing undesired light interference in the integrated system.