Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer.

Knowledge and investigation of therapeutic targets (responsible for drug efficacy) and the targeted drugs facilitate target and drug discovery and validation. Therapeutic Target Database (TTD, http://bidd.nus.edu.sg/group/ttd/ttd.asp) has been developed to provide comprehensive information about efficacy targets and the corresponding approved, clinical trial and investigative drugs. Since its last update, major improvements and updates have been made to TTD. In addition to the significant increase of data content (from 1894 targets and 5028 drugs to 2025 targets and 17 816 drugs), we added target validation information (drug potency against target, effect against disease models and effect of target knockout, knockdown or genetic variations) for 932 targets, and 841 quantitative structure activity relationship models for active compounds of 228 chemical types against 121 targets. Moreover, we added the data from our previous drug studies including 3681 multi-target agents against 108 target pairs, 116 drug combinations with their synergistic, additive, antagonistic, potentiative or reductive mechanisms, 1427 natural product-derived approved, clinical trial and pre-clinical drugs and cross-links to the clinical trial information page in the ClinicalTrials.gov database for 770 clinical trial drugs. These updates are useful for facilitating target discovery and validation, drug lead discovery and optimization, and the development of multi-target drugs and drug combinations.

Temperature is a fundamental parameter for all forms of lives. Natural evolution has resulted in organisms which have excellent thermoregulation capabilities in extreme climates. Bioinspired materials that mimic biological solution for thermoregulation have proven promising for passive radiative cooling. However, scalable production of artificial photonic radiators with complex structures, outstanding properties, high throughput, and low cost is still challenging. Herein, we design and demonstrate biologically inspired photonic materials for passive radiative cooling, after discovery of longicorn beetles’ excellent thermoregulatory function with their dual-scale fluffs. The natural fluffs exhibit a finely structured triangular cross-section with two thermoregulatory effects which effectively reflects sunlight and emits thermal radiation, thereby decreasing the beetles’ body temperature. Inspired by the finding, a photonic film consisting of a micropyramid-arrayed polymer matrix with random ceramic particles is fabricated with high throughput. The film reflects ∼95% of solar irradiance and exhibits an infrared emissivity >0.96. The effective cooling power is found to be ∼90.8 W⋅m−2and a temperature decrease of up to 5.1 °C is recorded under direct sunlight. Additionally, the film exhibits hydrophobicity, superior flexibility, and strong mechanical strength, which is promising for thermal management in various electronic devices and wearable products. Our work paves the way for designing and fabrication of high-performance thermal regulation materials.

Increasing numbers of proteins, nucleic acids and other molecular entities have been explored as therapeutic targets, hundreds of which are targets of approved and clinical trial drugs. Knowledge of these targets and corresponding drugs, particularly those in clinical uses and trials, is highly useful for facilitating drug discovery. Therapeutic Target Database (TTD) has been developed to provide information about therapeutic targets and corresponding drugs. In order to accommodate increasing demand for comprehensive knowledge about the primary targets of the approved, clinical trial and experimental drugs, numerous improvements and updates have been made to TTD. These updates include information about 348 successful, 292 clinical trial and 1254 research targets, 1514 approved, 1212 clinical trial and 2302 experimental drugs linked to their primary targets (3382 small molecule and 649 antisense drugs with available structure and sequence), new ways to access data by drug mode of action, recursive search of related targets or drugs, similarity target and drug searching, customized and whole data download, standardized target ID, and significant increase of data (1894 targets, 560 diseases and 5028 drugs compared with the 433 targets, 125 diseases and 809 drugs in the original release described in previous paper). This database can be accessed at http://bidd.nus.edu.sg/group/cjttd/TTD.asp.

Passive radiative cooling technology can cool down an object by reflecting solar light and radiating heat simultaneously. However, photonic radiators generally require stringent and nanoscale-precision fabrication, which greatly restricts mass production and renders them less attractive for large-area applications. A simple, inexpensive, and scalable electrospinning method is demonstrated for fabricating a high-performance flexible hybrid membrane radiator (FHMR) that consists of polyvinylidene fluoride/ tetraethyl orthosilicate fibers with numerous nanopores inside and SiO 2 microspheres randomly distributed across its surface. Even without silver back-coating, a 300 µm thick FHMR has an average infrared emissivity >0.96 and reflects ≈97% of solar irradiance. Moreover, it exhibits great flexibility and superior strength. The daytime cooling performance this device is experimentally demonstrated with an average radiative cooling power of 61 W m −2 and a temperature decrease up to 6 °C under a peak solar intensity of 1000 W m −2 . This performance is comparable to those of state-of-the-art devices.

Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2 preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.

Natural creatures have evolved elaborate photonic nanostructures on multiple scales and dimensions in a hierarchical, organized way to realize controllable absorption, reflection, or transmitting the desired wavelength of the solar spectrum. A bio-inspired strategy is a powerful and promising way for solar energy manipulation. This feature article presents the state-of-theart progress on bio-inspired photonic materials on this particular application. The article first briefly recalls the physical origins of natural photonic effects and catalogues the typical natural photonic prototypes including light harvesting, broadband reflection, selective reflection, and UV/IR response. Next, typical applications are categorized into two primary areas: solar energy utilization and reflection. Recent advances including solar-to-electricity, solar-to-fuels, solar-thermal (e.g., photothermal converters, infrared detectors, thermoelectric materials, smart windows, and solar steam generation) are highlighted in the first part. Meanwhile, solar energy reflection involving infrared stealth, radiative cooling, and micromirrors are also addressed. In particular, this article focuses on bioinspired design principles, structural effects on functions, and future trends. Finally, the main challenges and prospects for the next generation of bioinspired photonic materials are discussed, including new design concepts, emerging ideas, and possible strategies.

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