Palladium/norbornene-catalyzed diversified trifunctionalization of aryl-thianthreniums.

A novel Catellani-type conversion is reported using aryl-thianthreniums (aryl-TTs) instead of aryl halides. Three classes of ortho-dual C-H functionalization involving alkylation, amination, and deuterated methylation and five types of ipso-operation including alkenylation, cyanation, methylation, hydrogenation, and alkynylation all proceed well in this procedure. In this conversion, aryl-TTs exhibit satisfactory reactivity and feature the advantage that the leaving TT unit can be recovered. More strikingly, this finding represents a new chemistry conversion of aryl-TTs, wherein contiguous tri-functionalization in a single chemical manipulation is realized.

Hijacking monopolar spindle 1 (MPS1) for various cancer types by small molecular inhibitors: Deep insights from a decade of research and patents.

Monopolar spindle 1 (MPS1) has garnered significant attention due to its pivotal role in regulating the cell cycle. Anomalous expression and hyperactivation of MPS1 have been associated with the onset and advancement of diverse cancers, positioning it as a promising target for therapeutic interventions. This review focuses on MPS1 small molecule inhibitors from the past decade, exploring design strategies, structure-activity relationships (SAR), safety considerations, and clinical performance. Notably, we propose prospects for MPS1 degraders based on proteolysis targeting chimeras (PROTACs), as well as reversible covalent bonding as innovative MPS1 inhibitor design strategies. The objective is to provide valuable information for future development and novel perspectives on potential MPS1 inhibitors.

Rapid detection of multidrug resistance in tuberculosis using nanopore-based targeted next-generation sequencing: a multicenter, double-blind study.

Background: Resistance to anti-tuberculous drugs is a major challenge in the treatment of tuberculosis (TB). We aimed to evaluate the clinical availability of nanopore-based targeted next-generation sequencing (NanoTNGS) for the diagnosis of drug-resistant tuberculosis (DR-TB). Methods: This study enrolled 253 patients with suspected DR-TB from six hospitals. The diagnostic efficacy of NanoTNGS for detecting Mycobacterium tuberculosis and its susceptibility or resistance to first- and second-line anti-tuberculosis drugs was assessed by comparing conventional phenotypic drug susceptibility testing (pDST) and Xpert MTB/RIF assays. NanoTNGS can be performed within 12 hours from DNA extraction to the result delivery. Results: NanoTNGS showed a remarkable concordance rate of 99.44% (179/180) with the culture assay for identifying the Mycobacterium tuberculosis complex. The sensitivity of NanoTNGS for detecting drug resistance was 93.53% for rifampicin, 89.72% for isoniazid, 85.45% for ethambutol, 74.00% for streptomycin, and 88.89% for fluoroquinolones. Specificities ranged from 83.33% to 100% for all drugs tested. Sensitivity for rifampicin-resistant tuberculosis using NanoTNGS increased by 9.73% compared to Xpert MTB/RIF. The most common mutations were S531L (codon in E. coli) in the rpoB gene, S315T in the katG gene, and M306V in the embB gene, conferring resistance to rifampicin, isoniazid, and ethambutol, respectively. In addition, mutations in the pncA gene, potentially contributing to pyrazinamide resistance, were detected in 32 patients. Other prevalent variants, including D94G in the gyrA gene and K43R in the rpsL gene, conferred resistance to fluoroquinolones and streptomycin, respectively. Furthermore, the rv0678 R94Q mutation was detected in one sample, indicating potential resistance to bedaquiline. Conclusion: NanoTNGS rapidly and accurately identifies resistance or susceptibility to anti-TB drugs, outperforming traditional methods. Clinical implementation of the technique can recognize DR-TB in time and provide guidance for choosing appropriate antituberculosis agents.

Development of de-novo coronavirus 3-chymotrypsin-like protease (3CLpro) inhibitors since COVID-19 outbreak: A strategy to tackle challenges of persistent virus infection.

Although no longer a public health emergency of international concern, COVID-19 remains a persistent and critical health concern. The development of effective antiviral drugs could serve as the ultimate piece of the puzzle to curbing this global crisis. 3-chymotrypsin-like protease (3CLpro), with its substrate specificity mirroring that of the main picornavirus 3C protease and conserved across various coronaviruses, emerges as an ideal candidate for broad-spectrum antiviral drug development. Moreover, it holds the potential as a reliable contingency option to combat emerging SARS-CoV-2 variants. In this light, the approved drugs, promising candidates, and de-novo small molecule therapeutics targeting 3CLpro since the COVID-19 outbreak in 2020 are discussed. Emphasizing the significance of diverse structural characteristics in inhibitors, be they peptidomimetic or nonpeptidic, with a shared mission to minimize the risk of cross-resistance. Moreover, the authors propose an innovative optimization strategy for 3CLpro reversible covalent PROTACs, optimizing pharmacodynamics and pharmacokinetics to better prepare for potential future viral outbreaks.

Application of Miscanthus substrates in the cultivation of Ganoderma lingzhi.

Ganoderma lingzhi is a traditional Chinese medicine that has been used to improve health and longevity for thousands of years. It is usually cultivated on hardwood log- or sawdust-based formulations. Conversely, in this study, we used Miscanthus sacchariflorus (MSF), M. floridulus, and M. sinensis (MSS), fast-growing perennial grasses widely distributed in China, for G. lingzhi cultivation. Mycelial growth rate, activities of lignin-degrading enzymes on colonized mushroom substrates, and expression levels of CAZymes and laccase genes based on different substrates were analyzed. Total triterpenoids, sterols, and polysaccharides content of fruiting bodies obtained from different substrates were investigated. The activities of laccase and manganese peroxidase in mycelia increased in the MSF- and MSS-based formulations compared with that in the sawdust-based formulation. The results of mycelial growth- and cultivation-related experiments showed that the Miscanthus substrates could be used as the substrates for cultivating G. lingzhi. The content of active ingredients, namely triterpenoids, sterols, and polysaccharides, in fruiting bodies cultivated on the Miscanthus substrates did not decrease compared with those in substrate obtained from the sawdust-based formulation. Therefore, the present study provides alternative substrates for the cultivation of G. lingzhi, and a reference for better utilization of inexpensive substrate in future.

Genome-wide analysis of the MADS-box gene family in Lonicera japonica and a proposed floral organ identity model.

BACKGROUND: Lonicera japonica Thunb. is widely used in traditional Chinese medicine. Medicinal L. japonica mainly consists of dried flower buds and partially opened flowers, thus flowers are an important quality indicator. MADS-box genes encode transcription factors that regulate flower development. However, little is known about these genes in L. japonica. RESULTS: In this study, 48 MADS-box genes were identified in L. japonica, including 20 Type-I genes (8 Mα, 2 Mß, and 10 Mγ) and 28 Type-II genes (26 MIKCc and 2 MIKC*). The Type-I and Type-II genes differed significantly in gene structure, conserved domains, protein structure, chromosomal distribution, phylogenesis, and expression pattern. Type-I genes had a simpler gene structure, lacked the K domain, had low protein structure conservation, were tandemly distributed on the chromosomes, had more frequent lineage-specific duplications, and were expressed at low levels. In contrast, Type-II genes had a more complex gene structure; contained conserved M, I, K, and C domains; had highly conserved protein structure; and were expressed at high levels throughout the flowering period. Eleven floral homeotic MADS-box genes that are orthologous to the proposed Arabidopsis ABCDE model of floral organ identity determination, were identified in L. japonica. By integrating expression pattern and protein interaction data for these genes, we developed a possible model for floral organ identity determination. CONCLUSION: This study genome-widely identified and characterized the MADS-box gene family in L. japonica. Eleven floral homeotic MADS-box genes were identified and a possible model for floral organ identity determination was also developed. This study contributes to our understanding of the MADS-box gene family and its possible involvement in floral organ development in L. japonica.

Design, synthesis, and evaluation of novel pleuromutilin aryl acrylate derivatives as promising broad-spectrum antibiotics especially for combatting multi-drug resistant gram-negative bacteria.

The emergence of drug-resistant strains presents a grave challenge for traditional antibiotics, underscoring the exigency of exploring novel antibacterial drugs. To address this, the present study endeavors to design and synthesize a collection of pleuromutilin aromatic acrylate derivatives, guided by combination principles. The antibacterial activity and structure-activity relationship of these derivatives were evaluated, and most of the derivatives displayed moderate to excellent antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. Among these derivatives, 5g exhibited the strongest antibacterial activity, with MIC (minimum inhibitory concentration) values ranging from 1-32 µg/mL, and a MIC value against clinically isolated drug-resistant strains of 4-64 µg/mL. Additionally, 5g exhibited negligible cytotoxicity, superior anti-mycoplasma activity, and a greater propensity to perturb bacterial cell membranes. Notably, the administration of 5g resulted in an increased survival rate of MRSA (Methicillin-resistant Staphylococcus aureus)-infected mice, with an ED50 (median effective dose) value of 9.04 mg/kg. These results indicated the potential of 5g to be further developed as an antibacterial drug for the clinical treatment of drug-resistant bacterial infections.

Managing Comorbidities, Determinants and Disability at Start and End of TB Treatment under Routine Program Conditions in China.

Many patients with tuberculosis (TB) have comorbidities, risk determinants and disability that co-exist at diagnosis, during and after TB treatment. We conducted an observational cohort study in 11 health facilities in China to assess under routine program conditions (i) the burden of these problems at the start and end of TB treatment and (ii) whether referral mechanisms for further care were functional. There were 603 patients registered with drug-susceptible TB who started TB treatment: 84% were symptomatic, 14% had diabetes, 14% had high blood pressure, 19% smoked cigarettes, 10% drank excess alcohol and in 45% the 6 min walking test (6MWT) was abnormal. Five patients were identified with mental health disorders. There were 586 (97%) patients who successfully completed TB treatment six months later. Of these, 18% were still symptomatic, 12% had diabetes (the remainder with diabetes failed to complete treatment), 5% had high blood pressure, 5% smoked cigarettes, 1% drank excess alcohol and 25% had an abnormal 6MWT. Referral mechanisms for the care of comorbidities and determinants worked well except for mental health and pulmonary rehabilitation for disability. There is need for more programmatic-related studies in other countries to build the evidence base for care of TB-related conditions and disability.

The non-specific lipid transfer protein McLTPII.9 of Mentha canadensis is involved in peltate glandular trichome density and volatile compound metabolism.

Mentha canadensis L. is an important spice crop and medicinal herb with high economic value. The plant is covered with peltate glandular trichomes, which are responsible for the biosynthesis and secretion of volatile oils. Plant non-specific lipid transfer proteins (nsLTPs) belong to a complex multigenic family involved in various plant physiological processes. Here, we cloned and identified a non-specific lipid transfer protein gene (McLTPII.9) from M. canadensis, which may positively regulate peltate glandular trichome density and monoterpene metabolism. McLTPII.9 was expressed in most M. canadensis tissues. The GUS signal driven by the McLTPII.9 promoter in transgenic Nicotiana tabacum was observed in stems, leaves, and roots; it was also expressed in trichomes. McLTPII.9 was associated with the plasma membrane. Overexpression of McLTPII.9 in peppermint (Mentha piperita. L) significantly increased the peltate glandular trichome density and total volatile compound content compared with wild-type peppermint; it also altered the volatile oil composition. In McLTPII.9-overexpressing (OE) peppermint, the expression levels of several monoterpenoid synthase genes and glandular trichome development-related transcription factors-such as limonene synthase (LS), limonene-3-hydroxylase (L3OH), geranyl diphosphate synthase (GPPS), HD-ZIP3, and MIXTA-exhibited varying degrees of alteration. McLTPII.9 overexpression resulted in both a change in expression of genes for terpenoid biosynthetic pathways which corresponded with an altered terpenoid profile in OE plants. In addition, peltate glandular trichome density was altered in the OE plants as well as the expression of genes for transcription factors that were shown to be involved in trichome development in plants.

Discovery of Quaternized Pyridine-Thiazole-Pleuromutilin Derivatives with Broad-Spectrum Antibacterial and Potent Anti-MRSA Activity.

The quaternization of compounds has emerged as a promising molecular design strategy for the development of antibiotics. Herein, we report the design, synthesis, antibacterial activities, and structure-activity relationships of a series of novel pleuromutilin derivatives containing a quaternary amine C-14 side chain. Most of these derivatives exhibited broad-spectrum antibacterial activity against the tested bacteria. 10b was the most effective antibacterial agent that displayed excellent antibacterial activity against five clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, remarkable antimycoplasma activity, rapid bactericidal effects, and a strong ability to damage bacterial biofilms. Further mechanistic studies indicated that 10b destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, 10b exhibited high survival protection and potent in vivo antibacterial efficacy (ED50 = 4.94 mg/kg) in a mouse model of systemic MRSA infection. These findings suggest that 10b is a promising candidate for the treatment of multi-drug-resistant infectious diseases, especially MRSA infections.

Overexpression of a WRKY transcription factor McWRKY57-like from Mentha canadensis L. enhances drought tolerance in transgenic Arabidopsis.

BACKGROUND: Drought has become a major environmental problem affecting crop production. Members of the WRKY family play important roles in plant development and stress responses. However, their roles in mint have been barely explored. RESULTS: In this study, we isolated a drought-inducible gene McWRKY57-like from mint and investigated its function. The gene encodes a group IIc WRKY transcription factor, McWRKY57-like, which is a nuclear protein with a highly conserved WRKY domain and a C2H2 zinc-finger structure, and has transcription factor activity. Its expression levels were examined in different tissues of mint and under the treatment of mannitol, NaCl, abscisic acid, and methyl jasmonate. We found that McWRKY57-like overexpression in Arabidopsis significantly increased drought tolerance. Further studies showed that under drought stress, McWRKY57-like-overexpressing plants had higher chlorophyll, soluble sugar, soluble protein, and proline contents but lower water loss rate and malondialdehyde content than wild-type plants. Moreover, the activities of antioxidant enzymes catalase, superoxide dismutase, and peroxidase were enhanced in McWRKY57-like transgenic plants. Furthermore, qRT-PCR analysis revealed that the drought-related genes AtRD29A, AtRD29B, AtRD20, AtRAB18, AtCOR15A, AtCOR15B, AtKIN2, and AtDREB1A were upregulated in McWRKY57-like transgenic plants than in wild-type Arabidopsis under simulated drought conditions. CONCLUSION: These data demonstrated that McWRKY57-like conferred drought tolerance in transgenic Arabidopsis by regulating plant growth, osmolyte accumulation and antioxidant enzyme activities, and the expression of stress-related genes. The study indicates that McWRKY57-like plays a positive role in drought response in plants.

A Comprehensive Overview of the Antibiotics Approved in the Last Two Decades: Retrospects and Prospects.

Due to the overuse of antibiotics, bacterial resistance has markedly increased to become a global problem and a major threat to human health. Fortunately, in recent years, various new antibiotics have been developed through both improvements to traditional antibiotics and the discovery of antibiotics with novel mechanisms with the aim of addressing the decrease in the efficacy of traditional antibiotics. This manuscript reviews the antibiotics that have been approved for marketing in the last 20 years with an emphasis on the antibacterial properties, mechanisms, structure-activity relationships (SARs), and clinical safety of these antibiotics. Furthermore, the current deficiencies, opportunities for improvement, and prospects of antibiotics are thoroughly discussed to provide new insights for the design and development of safer and more potent antibiotics.

Luteolin Alleviates Oxidative Stress in Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke via Modulation of the TRPV1 and CYP2A13/NRF2 Signaling Pathways.

The current study aims to investigate the therapeutic potential of luteolin (Lut), a naturally occurring flavonoid found in various medicinal plants, for treating chronic obstructive pulmonary disease (COPD) through both in vitro and in vivo studies. The results demonstrated that Lut increased body weight, reduced lung tissue swelling and lung damage indices, mitigated systemic oxidative stress levels, and decreased alveolar fusion in cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD mice. Additionally, Lut was observed to downregulate the expression of the TRPV1 and CYP2A13 proteins while upregulating SIRT6 and NRF2 protein expression in CS + LPS-induced COPD mice and cigarette smoke extract (CSE)-treated A549 cells. The concentrations of total reactive oxygen species (ROS) and mitochondrial ROS in A549 cells induced by CSE significantly increased. Moreover, CSE caused a notable elevation of intracellular Ca2+ levels in A549 cells. Importantly, Lut exhibited inhibitory effects on the inward flow of Ca2+ and attenuated the overproduction of mitochondrial and intracellular ROS in A549 cells treated with CSE. In conclusion, Lut demonstrated a protective role in alleviating oxidative stress and inflammation in CS + LPS-induced COPD mice and CSE-treated A549 cells by regulating TRPV1/SIRT6 and CYP2A13/NRF2 signaling pathways.

Medicinal chemistry aspects and synthetic strategies of coumarin as aromatase inhibitors: an overview.

Coumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and the ease with which it may be transformed into a wide range of functionalized coumarins during synthesis, coumarin provides a privileged scaffold for medicinal chemists. As a result, many coumarin derivatives have been developed, synthesized, and evaluated to target a variety of therapeutic domains, thereby making it an attractive template for designing novel anti-breast cancer compounds. The main culprit in estrogen overproduction in the estrogen-dependent breast cancer (EDBC), is the enzyme aromatase (AR), and it is thought to be a significant target for the effective treatment of EDBC. Considering coumarins versatility, this review presents a detailed overview of diverse study of aromatase as a target for coumarins. An overview of structure-activity relationship analysis of coumarin core is also included so as to summarize the desired pharmacophoric features essential for design and development of aromatase inhibitors (AIs) using coumarin core. Identification of key synthesis techniques that could aid researchers in designing and developing novel analogues with significant anti-breast cancer properties along with their mechanism of action have also been covered in the current review.

Insights into stimuli-responsive diselenide bonds utilized in drug delivery systems for cancer therapy.

Due to the complexity and particularity of cancer cell microenvironments, redox responsive drug delivery systems (DDSs) for cancer therapy have been extensively explored. Compared with widely reported cancer treatment systems based on disulfide bonds, diselenide bonds have better redox properties and greater anticancer efficiency. In this review, the significance and application of diselenide bonds in DDSs are summarized, and the stimulation sensitivity of diselenide bonds is comprehensively reported. The potential and prospects for the application of diselenide bonds in next-generation anticancer drug treatment systems are extensively discussed.

Verbascoside: An Efficient and Safe Natural Antibacterial Adjuvant for Preventing Bacterial Contamination of Fresh Meat.

Inappropriate and disproportionate antibiotic use contributes immensely to the development of antibiotic resistance in bacterial species associated with food contamination. Therefore, alternative strategies to treat multidrug-resistant (MDR) bacterial infections are urgently needed. In this study, verbascoside was shown to exhibit excellent antibacterial activity and synergistic effects in combination with cell wall synthesis-inhibiting antibiotics, indicating that it can be used as an adjuvant to restore or increase the activity of antibiotics against resistant pathogens. In a mechanistic study, higher concentrations of verbascoside resulted in a longer lag phase and a lower specific exponential-phase growth rate of bacteria. Furthermore, verbascoside exerted its antimicrobial activity through multiple mechanisms, including cell membrane dysfunction, biofilm eradication and changes in cell morphology. The promising antibacterial activity and in vitro safety assessment results suggested that verbascoside can be used as a food additive for fresh meat preservation. Treatment with medium and high doses of verbascoside caused significant bacterial death in meat samples, slowed the spoilage rate, and extended the shelf life. Collectively, verbascoside is expected to be useful as an antibiotic adjuvant to prevent or treat resistant bacteria-related infections and an alternative novel antimicrobial additive in the food industry.

Comparative transcriptome analysis revealed candidate genes involved in fruiting body development and sporulation in Ganoderma lucidum.

Ganoderma lucidum is an edible mushroom highly regarded in the traditional Chinese medicine. To better understand the molecular mechanisms underlying fruiting body development in G. lucidum, transcriptome analysis based on RNA sequencing was carried out on different developmental stages: mycelium (G1); primordium (G2); young fruiting body (G3); mature fruiting body (G4); fruiting body in post-sporulation stage (G5). In total, 26,137 unigenes with an average length of 1078 bp were de novo assembled. Functional annotation of transcriptomes matched 72.49% of the unigenes to known proteins available in at least one database. Differentially expressed genes (DEGs) were identified between the evaluated stages: 3135 DEGs in G1 versus G2; 120 in G2 versus G3; 3919 in G3 versus G4; and 1012 in G4 versus G5. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs identified in G1 versus G2 revealed that, in addition to global and overview maps, enriched pathways were related to amino acid metabolism and carbohydrate metabolism. In contrast, DEGs identified in G2 versus G3 were mainly assigned to the category of metabolism of amino acids and their derivatives, comprising mostly upregulated unigenes. In addition, highly expressed unigenes associated with the transition between different developmental stages were identified, including those encoding hydrophobins, cytochrome P450s, extracellular proteases, and several transcription factors. Meanwhile, highly expressed unigenes related to meiosis such as DMC1, MSH4, HOP1, and Mek1 were also analyzed. Our study provides important insights into the molecular mechanisms underlying fruiting body development and sporulation in G. lucidum.

Regulatory Effect of Lactiplantibacillus plantarum 2-33 on Intestinal Microbiota of Mice With Antibiotic-Associated Diarrhea.

Diarrhea is one of the common adverse reactions in antibiotic treatment, which is usually caused by the imbalance of intestinal flora, and probiotics play an important role in the structure of intestinal flora. Therefore, this experiment studied the regulatory effect of Lactiplantibacillus plantarum 2-33 on antibiotic-associated diarrhea (AAD) mice. First, the AAD mice model was established by the mixed antibiotic solution of gentamicin sulfate and cefradine. Then, the physiological indexes and diarrhea of mice were observed and recorded by gastric perfusion of low dose (1.0 × 107 CFU/ml), medium dose (1.0 × 108CFU/ml), and high dose (1.0 × 109 CFU/ml) strain 2-33. 16S rRNA gene V3-V4 regions were sequenced in colon contents of mice in control group, model group, self-healing group, and experimental group, respectively, and the diversity of intestinal flora and gene function prediction were analyzed. The results showed that the intestinal flora of AAD mice was not significantly regulated by gastric perfusion of strain 2-33 to 7 days, but the relative abundance and diversity of intestinal flora of AAD mice were significantly improved by gastric perfusion to 14 days (p < 0.05). In addition, at the genus level, the relative abundance of Lactobacillus increased significantly, and the relative abundance of Enterococcus and Bacillus decreased significantly (p < 0.05). In addition, the regulation of strain 2-33 on intestinal flora of AAD mice was time- and dose-dependent, short-term gastric perfusion, and low dose had no significant effect (p > 0.05). Strain 2-33 can significantly increase the levels of anti-inflammatory cytokines IL-4 and IL-10, significantly decrease the levels of proinflammatory cytokines TNF-α and IFN-γ (p < 0.05), and can also adjust carbohydrate metabolism, amino acid metabolism, and energy metabolism to normal levels, thus accelerating the recovery of intestinal flora structure of AAD mice. In summary, strain 2-33 can improve the structure and diversity of intestinal flora of AAD mice, balance the level of substance and energy metabolism, and play a positive role in relieving diarrhea, maintaining and improving the intestinal microecological balance.

Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure-Activity Relationships Insights and Evolution Prospects.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that can change the expression of downstream target genes by catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3). Studies have found that EZH2 is highly expressed in a variety of tumor tissues and is closely related to the occurrence, development, invasion, and metastasis of tumors; therefore, EZH2 is becoming a new molecular target in antitumor therapy. Tazemetostat (EPZ-6438) was approved in 2020 as the first inhibitor targeting catalytic EZH2 for the treatment of epithelioid sarcoma. In addition, a variety of EZH2 inhibitors are being investigated in basic and clinical research for the treatment of tumors, and encouraging results have been obtained. This article systematically reviews the research progress on EZH2 inhibitors and proteolysis targeting chimera (PROTAC)-based EZH2 degradation agents with a focus on their design strategies, structure-activity relationships (SARs), and safety and clinical manifestations.

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy.

Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure-activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.