Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts.

Inhibition of cyclin-dependent kinases (CDKs) has become an effective therapeutic strategy for treating various diseases, especially cancer. Over almost three decades, although great efforts have been made to discover CDK inhibitors, many of which have entered clinical trials, only four CDK inhibitors have been approved. In the process of CDK inhibitor development, many difficulties and misunderstandings have hampered their discovery and clinical applications, which mainly include inadequate understanding of the biological functions of CDKs, less attention paid to pan- and multi-CDK inhibitors, nonideal isoform selectivity of developed selective CDK inhibitors, overlooking the metabolic stability of early discovered CDK inhibitors, no effective resistance solutions, and a lack of available combination therapy and effective biomarkers for CDK therapies. After reviewing the mechanisms of CDKs and the research progress of CDK inhibitors, this perspective summarizes and discusses these difficulties or lessons, hoping to facilitate the successful discovery of more useful CDK inhibitors.

Targeting the S2 Subsite Enables the Structure-Based Discovery of Novel Highly Selective Factor XIa Inhibitors.

FXIa inhibition has been a promising strategy for treating thrombotic diseases. Up to date, many small-molecule FXIa inhibitors have been identified; however, most of them exhibit undesirable selectivity over the homologous plasma kallikrein (PKal). By employing structure-based drug design strategies, we identified many novel selective FXIa inhibitors that have extra interactions with the S2 subsite of FXIa. Among them, compound 35 displayed good inhibitory activity against FXIa and high selectivity over PKal and even several other serine proteases. Additionally, 35 showed significant anticoagulant activity toward the intrinsic pathway without affecting the extrinsic pathway. In vivo, 35 exhibited significant antithrombotic activity without increasing the bleeding risk and obvious toxicity in mice, demonstrating that it could be a promising candidate for further research. This study first demonstrates the importance of the S2 subsite of FXIa, paving the way to design highly selective FXIa inhibitors for clinical uses.

Zinc enzymes in medicinal chemistry.

In humans, more than three hundred diverse enzymes that require zinc as an essential cofactor have been identified. These zinc enzymes have demonstrated different and important physiological functions and some of them have been considered as valuable therapeutic targets for drug discovery. Indeed, many drugs targeting a few zinc enzymes have been marketed to treat a variety of diseases. This review discusses drug discovery and drug development based on a dozen of zinc enzymes, including their biological functions and pathogenic roles, their best in class inhibitors (and clinical trial data when available), coordination and binding modes of representative inhibitors, and their implications for further drug design. The opportunities and challenges in developing zinc enzyme inhibitors for the treatment of human disorders are highlighted, too.

Effects of CTCP Modification on Microstructure and Wear Behavior of CTCP-NiCrBSi/Heat Resistant Steel Composite Layer.

A CTCP-NiCrBSi/heat resistant steel composite layer was designed and fabricated by vacuum fusion sintering. The structure of the composite layer was similar to reinforced concrete. Numerous reinforced regions with a cylindrical shape were evenly distributed in the heat resistant steel. Modified cast tungsten carbide particles (CTCP) reinforced NiCrBSi matrix composite constituted the reinforced region (CTCP-NiCrBSi). The microstructure of the composite layers was investigated by scanning electron microscope (SEM), energy dispersive x-ray spectrometer (EDS), and image analysis. The wear behavior of the composite layer was estimated on the ring-on-disc rig at a temperature range of room temperature (RT) to 800 °C in air. The microstructure and wear behavior of the composite layer with modified CTCP were compared with those with primary CTCP. The results showed that the poor chemical resistance of W2C and the interdiffusion of elements were responsible for the dissolution of unmodified CTCP in the molten NiCrBSi alloy. A WC outer shell formed on the surface of the CTCP after surface carburizing modification. The WC outer shell could effectively resist the dissolution of CTCP in NiCrBSi during the sintering process. The content of WC/W2C in modified CTCP-NiCrBSi increased by about 12.0 vol. % when compared with that in the primary CTCP-NiCrBSi. The wear rate of the composite layer with modified CTCP was lower than that with primary CTCP between RT and 700 °C. The wear rates of the composite layer decreased with increasing temperature from RT to 700 °C and increased above 700 °C.