Takanori Yamazaki

Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B‐cell lymphoma cells harboring gain‐of‐function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL‐AF9, MLL‐AF4, and AML1‐ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.

Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors

A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

Observation of M1 resonance in 206Pb using a highly linear polarized photon beam

Abstract More than twenty M1 states were discovered in 206 Pb from 6.5 to 8.1 MeV with a high-resolution NRF experiment that used a highly linear-polarized photon beam generated by laser-Compton backscattering. The total reduced transition probability of ΣB ( M 1 ↑) = 17.4 ± 5.6 μ N 2 agreed well with QPM calculation (16.1 μ N 2 ) and previous tagged photon experiment (19 ± 2 μ N 2 ). a fine structure of two bumps at 7.2 and 7.9 MeV which was reproduced reasonably by the QPM calculation was clearly observed in the isovector M1 strength distribution.

The operation of a superconducting wiggler at TERAS

A superconducting wiggler has been successfully installed at the ETL 800 MeV electron storage ring facility (TERAS). The operation of the wiggler at magnetic field strengths of 5 T with electron beam energy of 750 MeV has been accomplished. The wiggler has been designed and constructed to produce synchrotron radiation with critical photon energy around 3 keV for scientific, industrial and medical applications. We report here experiments that demonstrate the possibility of stable operation of a superconducting wiggler in a small storage ring.

Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.

Pile-up correction of pulse height spectrum measured by a Ge detector to a pulsed beam of high energy photons

A peak pile-up correction of the output pulses measured by a Ge detector is necessary for a quantitative measurement of a pulsed beam of high energy photons which are produced by Compton backscattering of pulsed laser light with relativistic electrons in a synchrotron storage ring. The peak pile-up causes not only a distortion of pulse height distribution measured by a Ge detector but also affects quantitative measurements based on integrating the area under the pulse height spectrum. In order to correct the peak pile-up, a Monte Carlo simulation has been applied to calculate the pile-up spectrum by superposing double pulse or triple pulse coincidences with different pulse heights and different time delays. It is assumed that the output pulses are randomly generated in time within one burst of the pulsed laser light. An undistorted pulse height spectrum necessary for the simulation has been obtained from a low counting rate experiment which has a negligible pile-up. A good agreement between the simulated spectrum and the experimental spectrum using different pile-up rates has been obtained. After fitting the experimental data by use of the simulated spectrum, the measured spectrum call be resolved into single, double and triple pile-up components. This results in a quantitatively corrected peak pile-up at different counting rates.