Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361).

The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA.

A benchmarking method to evaluate the accuracy of a commercial proton monte carlo pencil beam scanning treatment planning system.

AcurosPT is a Monte Carlo algorithm in the Eclipse 13.7 treatment planning system, which is designed to provide rapid and accurate dose calculations for proton therapy. Computational run-time in minimized by simplifying or eliminating less significant physics processes. In this article, the accuracy of AcurosPT was benchmarked against both measurement and an independent MC calculation, TOPAS. Such a method can be applied to any new MC calculation for the detection of potential inaccuracies. To validate multiple Coulomb scattering (MCS) which affects primary beam broadening, single spot profiles in a Solidwater® phantom were compared for beams of five selected proton energies between AcurosPT, measurement and TOPAS. The spot Gaussian sigma in AcurosPT was found to increase faster with depth than both measurement and TOPAS, suggesting that the MCS algorithm in AcurosPT overestimates the scattering effect. To validate AcurosPT modeling of the halo component beyond primary beam broadening, field size factors (FSF) were compared for multi-spot profiles measured in a water phantom. The FSF for small field sizes were found to disagree with measurement, with the disagreement increasing with depth. Conversely, TOPAS simulations of the same FSF consistently agreed with measurement to within 1.5%. The disagreement in absolute dose between AcurosPT and measurement was smaller than 2% at the mid-range depth of multi-energy beams. While AcurosPT calculates acceptable dose distributions for typical clinical beams, users are cautioned of potentially larger errors at distal depths due to overestimated MCS and halo implementation.

Characterization of the microstructure of GaP films grown on {111} Si by liquid phase epitaxy.

The development of a cost-effective Si based platform on which III-V's can be grown is of great interest. This work investigates the morphology of gallium phosphide (GaP) films grown on {111} silicon (Si) substrates by means of liquid phase epitaxy in a tin (Sn) - based solvent bath. Two types of single-crystal {111} Si substrates were used; the first type was oriented exactly along the ⟨111⟩ surface (no-miscut) and the second was miscut by 4°. The growth rate of the GaP films was found to be markedly different for the two types of substrates; the GaP films on the miscut Si substrate grew ∼4 times faster than those on the no-miscut substrate. The GaP films grew epitaxially on both types of substrates, but contained Si and Sn as inclusions. In the case of the no-miscut substrate, a number of large Sn particles were incorporated at the GaP/Si interface. As a result, these interfacial Sn particles affected the strain state of the GaP films dramatically, which, in turn, manifested itself in the form of a duplex microstructure that consists of strained and strain-free regions.

Thin film solar cell design based on photonic crystal and diffractive grating structures.

In this paper we present novel light trapping designs applied to multiple junction thin film solar cells. The new designs incorporate one dimensional photonic crystals as band pass filters that reflect short light wavelengths (400 - 867 nm) and transmit longer wavelengths(867 -1800 nm) at the interface between two adjacent cells. In addition, nano structured diffractive gratings that cut into the photonic crystal layers are incorporated to redirect incoming waves and hence increase the optical path length of light within the solar cells. Two designs based on the nano structured gratings that have been realized using the scattering matrix and particle swarm optimization methods are presented. We also show preliminary fabrication results of the proposed devices.