Acoustofluidic localization of sparse particles on a piezoelectric resonant sensor for nanogram-scale mass measurements.

The ability to weigh microsubstances present in low concentrations is an important tool for environmental monitoring and chemical analysis. For instance, developing a rapid analysis platform that identifies the material type of microplastics in seawater would help evaluate the potential toxicity to marine organisms. In this study, we demonstrate the integration of two different techniques that bring together the functions of sparse particle localization and miniaturized mass sensing on a microelectromechanical system (MEMS) chip for enhanced detection and minimization of negative measurements. The droplet sample for analysis is loaded onto the MEMS chip containing a resonant mass sensor. Through the coupling of a surface acoustic wave (SAW) from a SAW transducer into the chip, the initially dispersed microparticles in the droplet are localized over the detection area of the MEMS sensor, which is only 200 µm wide. The accreted mass of the particles is then calibrated against the resulting shift in resonant frequency of the sensor. The SAW device and MEMS chip are detachable after use, allowing the reuse of the SAW device part of the setup instead of the disposal of both parts. Our platform maintains the strengths of noncontact and label-free dual-chip acoustofluidic devices, demonstrating for the first time an integrated microparticle manipulation and real-time mass measurement platform useful for the analysis of sparse microsubstances.

Technique and Circuit for Contactless Readout of Piezoelectric MEMS Resonator Sensors.

A technique and electronic circuit for contactless electromagnetic interrogation of piezoelectric micro-electromechanical system (MEMS) resonator sensors are proposed. The adopted resonator is an aluminum-nitride (AlN) thin-film piezoelectric-on-silicon (TPoS) disk vibrating in radial contour mode at about 6.3 MHz. The MEMS resonator is operated in one-port configuration and it is connected to a spiral coil, forming the sensor unit. A proximate electronic interrogation unit is electromagnetically coupled through a readout coil to the sensor unit. The proposed technique exploits interleaved excitation and detection phases of the MEMS resonator. A tailored electronic circuit manages the periodic switching between the excitation phase, where it generates the excitation signal driving the readout coil, and the detection phase, where it senses the transient decaying response of the resonator by measuring through a high-impedance amplifier the voltage induced back across the readout coil. This approach advantageously ensures that the readout frequency of the MEMS resonator is first order independent of the interrogation distance between the readout and sensor coils. The reported experimental results show successful contactless readout of the MEMS resonator independently from the interrogation distance over a range of 12 mm, and the application as a resonant sensor for ambient temperature and as a resonant acoustic-load sensor to detect and track the deposition and evaporation processes of water microdroplets on the MEMS resonator surface.

Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RETV804M Kinase.

A combination of focused library and virtual screening, hit expansion, and rational design has resulted in the development of a series of inhibitors of RETV804M kinase, the anticipated drug-resistant mutant of RET kinase. These agents do not inhibit the wild type (wt) isoforms of RET or KDR and therefore offer a potential adjunct to RET inhibitors currently undergoing clinical evaluation.

Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade.

RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.

Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.

We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.