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.

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

The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions.

Blocking Non-enzymatic Functions by PROTAC-Mediated Targeted Protein Degradation.

Proteolysis-targeting chimeras (PROTACs) is a fast-growing technology providing many strengths over inhibition of protein activity directly and is attracting increasing interest in new drug discovery and development. However, efficiently identifying potent and drug-like degraders is still challenging in the development of PROTACs. Complementary to traditional PROTACs, several emerging types of PROTACs, such as homobivalent PROTACs based on two E3 ligases (e.g., CRBN, VHL, MDM2, TRIM24), chemical- or biological-based trivalent/multitargeted PROTACs, and covalent PROTACs, are rising for targeted protein degradation. These new types of PROTACs have several advantages over the traditional PROTACs including high selectivity, low toxicity, better therapeutic effects, and so on. In this perspective, we will summarize the latest development of representative PROTACs focusing on research mainly in past 10 years and discuss their advantages and disadvantages. Moreover, the outlook and perspectives on the associated challenges and future directions will be provided.

Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation.

Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor 4, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.

Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13

Prostate cancer (PC), the fifth leading cause of cancer-related mortality worldwide, is known as metastatic bone cancer when it spreads to the bone. Although there is still no effective treatment for advanced/metastatic PC, awareness of the molecular events that contribute to PC progression has opened up opportunities and raised hopes for the development of new treatment strategies. Androgen deprivation and androgen-receptor-targeting therapies are two gold standard treatments for metastatic PC. However, acquired resistance to these treatments is a crucial challenge. Due to the role of protein kinases (PKs) in the growth, proliferation, and metastases of prostatic tumors, combinatorial therapy by PK inhibitors may help pave the way for metastatic PC treatment. Additionally, PC is known to have epigenetic involvement. Thus, understanding epigenetic pathways can help adopt another combinatorial treatment strategy. In this study, we reviewed the PKs that promote PC to advanced stages. We also summarized some PK inhibitors that may be used to treat advanced PC and we discussed the importance of epigenetic control in this cancer. We hope the information presented in this article will contribute to finding an effective treatment for the management of advanced PC.

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Targeting Protein Kinases and Epigenetic Control as Combinatorial Therapy Options for Advanced Prostate Cancer Treatment

Protein kinases have been highly fruitful targets for cancer drug discovery in the past two decades, while most of these drugs bind to the "adenosine triphosphate (ATP)-site" and inhibit kinase catalytic activity. Recently, accumulated evidence suggests that kinases possess functions beyond catalysis through their scaffolds, and the scaffolding functions could play critical roles in multiple cellular signaling and cell fate controls. Small molecules modulating the noncatalytic functions of kinases are rarely reported but emerge as new promising therapeutic strategies for various diseases. Herein, we summarize the characterized noncatalytic functions of kinases, and highlight the recent progress on developing small-molecule modulators of the noncatalytic functions of kinases. Mechanisms and characteristics of different kinds of modulators are also discussed. It is also speculated that targeting the noncatalytic functions would represent a new direction for kinase-based drug discovery.

Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

Abstract It is still a challenge to achieve large-area preparation of robust superhydrophobic surfaces with strong mechanical stability. Here, a simple and low-cost method to prepare robust decoupling superhydrophobic coatings on aluminum (Al) alloys substrate has been presented. The superhydrophobicity and robustness of decoupling coatings are realized by structuring surfaces at two different length scales, with nanostructures for superhydrophobicity and microstructures for robustness. This prepared decoupling coating shows promising superhydrophobicity, with water contact angle (CA) of ∼158.4° and roll off angle (RA) of ∼3°. It also exhibits high repellency for impacting water droplets. Notably, the decoupling coating processes outstanding adhesion strength on the substrate after tape-peeling and cross-cut tests, also with promising wear resistantance after sandpaper abrasion and wear test. The friction coefficient of this decoupling coating is only ∼0.2. In addition, the robust decoupling superhydrophobic coating is applied to underwater buoyancy enhancement and fluid resistance reduction (drag reduction rate ∼30.09%). This decoupling superhydrophobic coating also displays promising self-cleaning and antifouling properties. Moreover, benefitting from the photocatalytic property of TiO 2 , this decoupling coating is also exploited for degrading organics to achieve seawater purification. This obtained decoupling superhydrophobic coating is expected to apply on other solids in marine fields, and the simple and eco-friendly method develops the potential practical application. 

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Large-scale fabrication of decoupling coatings with promising robustness and superhydrophobicity for antifouling, drag reduction, and organic photodegradation

Kaijie Zhou

Papers

Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

Large-scale fabrication of decoupling coatings with promising robustness and superhydrophobicity for antifouling, drag reduction, and organic photodegradation