Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

Scale-adaptive three-dimensional imaging using Risley-prism-based coherent lidar.

We present a scale-adaptive three-dimensional (3D) imaging architecture for coherent light detection and ranging (lidar) that incorporates Risley-prism-based beam scanning. An inverse design paradigm from beam steering to prism rotation is developed for demand-oriented beam scan pattern generation and prism motion law formulation, which allows the lidar to perform 3D imaging with adaptive scale and configurable resolution. By combining flexible beam manipulation with simultaneous distance and velocity measurement, the proposed architecture can achieve both large-scale scene reconstruction for situational awareness and small-scale object identification against long range. The experiment results demonstrate that our architecture enables the lidar to recover a 3D scene in a ±30° field of view and also focus on distant objects at over 500 m with spatial resolution up to 1.1 cm.

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

Multiview three-dimensional imaging using a Risley-prism-based spatially adaptive virtual camera field.

We present a three-dimensional (3D) imaging system that incorporates a stationary camera and Risley prisms. By planning prism rotation to generate a spatially adaptive virtual camera field, the system allows multiple virtual cameras in the field to capture any object from different perspectives for 3D reconstruction. An automatic virtual camera calibration method based on perspective projection and geometric optics is developed to enable virtual camera field construction and characterization. Moreover, a 3D computational reconstruction framework is proposed for multiview information fusion using the virtual camera field. This framework combines nonlinear distortion correction with epipolar geometry computation to efficiently perform image rectification and stereo matching, which can further facilitate 3D object reconstruction through multiview triangulation. The experiments on synthetic and real data validate the feasibility and flexibility of our 3D imaging technique.

Self-calibration method for rotating Risley prism main sections based on chromatic dispersion characteristics of the Fourier spectrum.

To address the main section misalignment of rotating Risley prisms in a camera imaging system, a zero calibration method for a Risley prism main section is proposed according to the dispersion characteristics of the prisms-camera imaging. The principal component analysis method and the Radon transform method are combined to establish an effective mapping relationship between the prism main section positions and the prismatic dispersion characteristics using the camera dispersion image as references. The estimation of the dispersion direction was realized by referring to the motion blur estimation method and verified by experiment. As a result, the target-free self-calibration of the prism main sections in the camera coordinate system can be carried out under a prisms-camera intact assembly mode.

Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies.

Compact three-dimensional computational imaging using a dynamic virtual camera.

We present a three-dimensional (3D) computational imaging architecture based on the imaging principle of a dynamic virtual camera, which enables the spatial reconstruction using a single camera and a compact wedge prism device. By rotating the prism for camera boresight adjustment, the proposed system can capture an object from different viewpoints. Each captured image appears to be recorded directly with one virtual camera moving in a certain path, facilitating the computational process for stereo matching and profile reconstruction. The experimental results have demonstrated that our architecture allows a compact and flexible system to achieve 3D imaging performance competitive to conventional stereovision.

Risley-prism-based visual tracing method for robot guidance.

A visual tracing model based on Risley prisms is proposed in this paper. Combined with the boresight adjusting technology and the visual detection technology, a new visual system is established. Placing Risley prisms in front of the camera, the field of view of the camera can be dynamically adjusted so that the imageable area of this camera is expanded greatly. Two real-time visual tracing strategies for dynamic targets are proposed, which effectively avoid the problems of target loss and tracking instability. The deviations between the reference trajectory generated by the manipulator and the actual trajectory detected by our visual system are measured. Experimental results show that the deviations are less than 1.5% in the 250 mm motion space of the manipulator. It is verified that the visual system can be used to guide robots with high precision, which provides a potential method for robot navigation.

Risley-prism-based tracking model for fast locating a target using imaging feedback.

Fast imaging tracking technology exhibits attractive application prospects in the emerging fields of target tracking and recognition. Smart and compact tracking model with fast and flexible tracking strategy can play a decisive role in improving system performance. In this paper, an effective imaging tracking model from a target to a rotation Risley prism pair embedded with a camera is derived by the beam vector propagation method. A boresight adjustment strategy using the inverse ray tracing and iterative refinement method is established to accomplish the function of fast locating a target. The influence of system parameters on boresight adjustment accuracy and even the dynamic characteristics of the tracking system are investigated to reveal the coupling mechanisms between prism rotation and imaging feedback. The root-mean-square tracking error is below 4.5 pixels by just once adjustment in the static target experiment, while the error in the dynamic experiment is below 8.5 pixels for a target moving at the speed of 50 mm/s, which validates the feasibility of the proposed method for fast imaging tracking applications.

Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors.

Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4'-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [indoline-3,4'-piperidine] derivatives A1-A4 using Neratinib and spiro [indoline-3, 4'-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain B1-B7 and replaced indoline with benzmorpholine to get C1-C4 and D1-D2. We synthesized these compounds and evaluated their residual activities under 0.5 M drug concentration on EGFR and ERBB2. Most of compounds showed stronger inhibition on EGFR-wt and ERBB2, in which A1-A4 showed excellent inhibitory activity with inhibition percentage on EGFR-wt kinase of 7%, 6%, 19%, 27%, respectively and 9%, 5%, 12%, 34% on ERBB2 kinase compared with 2% and 6% of Neratinib.

Prelocation image stitching method based on flexible and precise boresight adjustment using Risley prisms.

A prelocation image stitching method is proposed for the scan imaging system using Risley prisms. By confining the feature-based stitching procedure to several prelocated overlap areas in multiple subregion images, the proposed method reduces the computational complexity of feature extraction and image registration. Experiment results and analysis have validated the feasibility and robustness of the overlap prelocation algorithm, which can enhance the image stitching efficiency by 21.89% at least and by 39.38% at most. In addition, the composite image obtained from the prelocation stitching procedure can achieve a large field of view while maintaining high resolution.

Double-wedge prism imaging tracking device based on the adaptive boresight adjustment principle.

A double-wedge prism device has been used in various imaging detection applications due to its high precision and strong anti-disturbance capability. In this paper, a self-adaptation double-wedge prism boresight adjustment principle suitable for both far-field and near-field target tracking is proposed. In order to realize this application, an adaptive variable boresight imaging tracking device is designed specifically. Then a tracking error model is established, and dynamic simulation, error evaluation, and sensitivity analysis are carried out according to the design objective. The experimental results show that the pitch angle deviation and azimuth angle deviation of the device are less than 6', and the blind zone can be eliminated by adding a third wedge prism, thus achieving high-precision boresight adjustment and tracking.

Rotation double prisms steered by noncircular gear pairs to scan specified nonlinear trajectories.

In order to scan some specified nonlinear motion trajectories with high accuracy, simple control process, and good stability, we propose a method to design the drive mechanism of the rotation double-prism scanner, which can transfer the nonlinear motor control to the profile design of corresponding noncircular gear pairs. Given a nonlinear target trajectory, this method can successfully change the complicated nonlinear motion of the motor to the more operative uniform rotation. The simulation and experiment results show that the tracking error is less than 0.981 mm in the distance of 500 mm between the actual tracking trajectory and the original one. The proposed drive mechanical setup offers a perfect alternative to the nonlinear control design of the rotation double-prism scanner.

Investigation of scan errors in the three-element Risley prism pair.

In this paper, the error analysis model for the three-element Risley-prism scan system (TRSS) is established, and categories of error sources are redefined. The impact of each error on the pointing accuracy is graphically presented with analytical and numerical results. The analysis method can be implemented to any Risley-prism beam scan system. For thin prisms, an error compensation algorithm for the TRSS is developed to accomplish high-accuracy beam scanning, which can be referred to the error calibration of the TRSS.

Laser coarse-fine coupling tracking by cascaded rotation Risley-prism pairs.

Rotation Risley prisms are increasingly used for laser tracking due to high precision and good dynamic performance. In this paper, a novel laser coarse-fine coupling tracking method based on two pairs of rotation Risley prisms is proposed to perform the forward and inverse tracking function. The second pair of rotation Risley prisms with narrower wedge angle can achieve higher precision tracking with narrower field of view than the first one, enriching the coarse-fine coupling tracking trajectory patterns. Moreover, an inverse algorithm based on the two-step method and Newton's iterative method is applied to solve the inverse issue for laser coarse-fine coupling tracking. Two cases further demonstrate that the motion switching strategy executed with the inverse solutions can steer the beam to track the desired motion trajectory. An experiment validates the availability of the cascaded rotation Risley-prism pairs to perform the laser coarse-fine coupling tracking function.

Forward and inverse solutions for three-element Risley prism beam scanners.

Scan blind zone and control singularity are two adverse issues for the beam scanning performance in double-prism Risley systems. In this paper, a theoretical model which introduces a third prism is developed. The critical condition for a fully eliminated scan blind zone is determined through a geometric derivation, providing several useful formulae for three-Risley-prism system design. Moreover, inverse solutions for a three-prism system are established, based on the damped least-squares iterative refinement by a forward ray tracing method. It is shown that the efficiency of this iterative calculation of the inverse solutions can be greatly enhanced by a numerical differentiation method. In order to overcome the control singularity problem, the motion law of any one prism in a three-prism system needs to be conditioned, resulting in continuous and steady motion profiles for the other two prisms.

Performance characterization of scanning beam steered by tilting double prisms.

A pair of orthogonal tilting double prisms with a tracking precision better than submicroradian order exhibits a good application potential in laser tracking fields. In the paper, the beam scanning performance determined by both the structure parameters and the tilting motions of two prisms is overall investigated. The functional relation between the structure parameters and the exact beam scanning range is established, the capability of high-accuracy beam steering is validated together with the investigation of the scanning error sources and the nonlinear control laws, and the beam shape distortion degree under multi-parameter combinations is demonstrated. These studies can provide important references for the development of tilting double prisms.

Beam distortion of rotation double prisms with an arbitrary incident angle.

The distortion of beam shape in rotation Risley prisms is discussed in this paper. Using the ray-tracing method based on vector refraction theorem, a rigorous theoretical model of beam distortion with an arbitrary incident angle is established to explore the influencing factors. For a specified double-prism pair, the emergent beam is squeezed in one direction while stretched in the mutual perpendicular direction, the distortion of which is determined by the relative rotation angle. Moreover, the distortion of beam shape is greatly influenced by the wedge angles and the refractive indices of the prisms, as well as different double-prism configurations, while uncorrelated to the prism thickness and the distance between two prisms. This paper demonstrates the regular change of the beam shape with multiparameter variations in rotation double prisms, which can be applied to the design of rotation double-prism systems.

Investigation of beam steering performances in rotation Risley-prism scanner.

Rotation Risley-prism scanner appears to be the most promising solution to high-accuracy beam scanning and target tracking. In the paper, some important issues crucial to the function implementation are thoroughly investigated. First the forming law of scan blind zone relative to double-prism structural parameters is explored by a quantitative analysis method. Then the nonlinear relationship between the rotation speeds of double prisms and the change rate of beam deviation angle is presented, and the beam scan singularity is indicated as an essential factor that confines the beam scan region. Finally, the high-accuracy radial scan theory is verified to illustrate the important application owing to the high reduction ratio from the rotation angles of double prisms to the deviation angles of the emergent beam. The research not only reveals the inner mechanisms of the Risley-prism beam scanning in principle, but also provide a foundation for the nonlinear control of various beam scan modes.

Tilting double-prism scanner driven by cam-based mechanism.

A pair of orthogonal tilting prisms has been explored in our previous work to perform the orientation and position tracking function with tracking accuracy better than submicroradian order. Crucial to the function implementation, however, is the real-time nonlinear control of the tilting angles of double prisms for tracking a given target trajectory. In previous papers [Proc. SPIE5892, 1-5 (2005).PSISDG0277-786X; Appl. Opt.45, 8063 (2006).PSISDG0277-786X; Proc. SPIE6709, 41 (2007).PSISDG0277-786X; Appl. Opt.51, 356 (2011).10.1364/AO.51.000356APOPAI1559-128X; Appl. Opt.53, 3712 (2014).10.1364/AO.53.003712APOPAI1559-128X], a new driving method by a cam-based mechanism, which can transfer the control problem to the design of corresponding cam configuration, is investigated. The design process of a cam-based mechanism is explained from the mapping relation between the tilting angles of a prism and the configuration curve of a corresponding cam. Based on the designed cam-based mechanism, a tracking error less than 0.375% is depicted between the tracking trajectory and the original one. Moreover, the dynamic characteristic of the tracking mechanism is discussed in detail as well as the impacts of different tilting speeds on the tracking trajectory. The proposed tracking mechanism of a tilting double-prism scanner can create a new avenue for passively tracking a given target.