Recent Progress in CDK4/6 Inhibitors and PROTACs.

Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly in treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This review provides an in-depth analysis of the action mechanism and recent advancements in CDK4/6 inhibitors, categorizing them based on their structural characteristics and origins. Furthermore, it explores proteolysis targeting chimers (PROTACs) targeting CDK4/6. We hope that this review could be of benefit for further research on CDK4/6 inhibitors and PROTACs.

Sensory root demyelination: Transforming touch into pain.

The normal feeling of touch is vital for nearly every aspect of our daily life. However, touching is not always felt as touch, but also abnormally as pain under numerous diseased conditions. For either mechanistic understanding of the faithful feeling of touch or clinical management of chronic pain, there is an essential need to thoroughly dissect the neuropathological changes that lead to painful touch or tactile allodynia and their corresponding cellular and molecular underpinnings. In recent years, we have seen remarkable progress in our understanding of the neural circuits for painful touch, with an increasing emphasis on the upstream roles of non-neuronal cells. As a highly specialized form of axon ensheathment by glial cells in jawed vertebrates, myelin sheaths not only mediate their outstanding neural functions via saltatory impulse propagation of temporal and spatial precision, but also support long-term neuronal/axonal integrity via metabolic and neurotrophic coupling. Therefore, myelinopathies have been implicated in diverse neuropsychiatric diseases, which are traditionally recognized as a result of the dysfunctions of neural circuits. However, whether myelinopathies can transform touch into pain remains a long-standing question. By summarizing and reframing the fragmentary but accumulating evidence so far, the present review indicates that sensory root demyelination represents a hitherto underappreciated neuropathological change for most neuropathic conditions of painful touch and offers an insightful window into faithful tactile sensation as well as a potential therapeutic target for intractable painful touch.

Structure-activity relationships and antiproliferative effects of 1,2,3,4-4H-quinoxaline derivatives as tubulin polymerization inhibitors.

Colchicine binding site inhibitors (CBSIs) hold great potential for the treatment of various tumors and they can overcome multidrug resistance which the existing tubulin inhibitors such as paclitaxel and vinorelbine are faced with. Herein, we report the design, synthesis and biological evaluation of a series of tetrahydro-quinoxaline derivatives as colchicine binding site inhibitors. All the synthesized compounds were evaluated for their in vitro antiproliferative activities against HT-29 and Hela cancer cell lines, and most of the target compounds demonstrated moderate to strong activities towards two tumor cell lines. In addition, the structure-activity relationships of these derivatives were also discussed. Among them, compounds 11a and 11b showed the most potent activities. Moreover, compound 11a inhibited the tubulin polymerization in both cell-free and cellular assays. Further profiling of compound 11a revealed that it arrested cell cycle in G2/M and induced cell apoptosis in a dose-dependent manner. Furthermore, molecular docking study proved that compound 11a acted on the colchicine binding site. Therefore, 11a is a promising candidate for the discovery of colchicine binding site inhibitors.

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries.

Nerve injury-induced chronic pain has been an urgent problem for both public health and clinical practice. While transition to chronic pain is not an inevitable consequence of nerve injuries, the susceptibility/resilience factors and mechanisms for chronic neuropathic pain after nerve injuries still remain unknown. Current preclinical and clinical studies, with certain notable limitations, have shown that major histocompatibility complex class II-restricted T helper (Th) cells is an important trigger for nerve injury-induced chronic tactile allodynia, one of the most prevalent and intractable clinical symptoms of neuropathic pain. Moreover, the precise pathogenic neuroimmune interfaces for Th cells remain controversial, not to mention the detailed pathogenic mechanisms. In this review, depending on the biology of Th cells in a neuroimmunological perspective, we summarize what is currently known about Th cells as a trigger for chronic tactile allodynia after nerve injuries, with a focus on identifying what inconsistencies are evident. Then, we discuss how an interdisciplinary perspective would improve the understanding of Th cells as a trigger for chronic tactile allodynia after nerve injuries. Finally, we hope that the expected new findings in the near future would translate into new therapeutic strategies via targeting Th cells in the context of precision medicine to either prevent or reverse chronic neuropathic tactile allodynia.

EIF3J-AS1 promotes glioma cell growth via up-regulating ANXA11 through sponging miR-1343-3p.

BACKGROUND: Glioma is one prevalent malignant tumor originates from the central nervous system. Dysregulation of long non-coding RNAs (lncRNAs) has been found to be a molecular signature behind the pathology of a variety of cancers, including glioma. EIF3J antisense RNA 1 (EIF3J-AS1) is a novel lncRNA, whose performance in carcinogenesis has been unfolded. Nevertheless, the role of EIF3J-AS1 has never been investigated in glioma. METHODS: qRT-PCR analysis was adopted to evaluate the relative levels of RNAs. In vitro functional assays, including colony formation, EdU, TUNEL and caspase-3/8/9 activity assays were conducted to study the impacts of EIF3J-AS1 on glioma. Dual-luciferase activity assays, RNA pull down assay and RIP assay were performed to elucidate molecular interplay among genes. RESULTS: EIF3J-AS1 was overexpressed in glioma cell lines. Knockdown of EIF3J-AS1 hampered glioma malignant phenotypes. MiR-1343-3p could bind to EIF3J-AS1. Moreover, miR-1343-3p targeted Annexin A11 (ANXA11) in its 3'UTR region. Mechanistically, EIF3J-AS1 relieved ANXA11 from miR-1343-3p silencing in the EIF3J-AS1/miR-1343-3p/ANXA11 RNA induced silencing complex (RISC), thus eliciting promoting effects on glioma progression. MiR-1343-3p inhibitor and ANXA11 overexpression offset the inhibitory impacts of EIF3J-AS1 silencing on glioma development. CONCLUSION: EIF3J-AS1/miR-1343-3p/ANXA11 axis significantly affected biological behaviors in glioma, suggesting new therapeutic target for glioma treatment.

CD4+ αß T cell infiltration into the leptomeninges of lumbar dorsal roots contributes to the transition from acute to chronic mechanical allodynia after adult rat tibial nerve injuries.

BACKGROUND: Antigen-specific and MHCII-restricted CD4+ αß T cells have been shown or suggested to play an important role in the transition from acute to chronic mechanical allodynia after peripheral nerve injuries. However, it is still largely unknown where these T cells infiltrate along the somatosensory pathways transmitting mechanical allodynia to initiate the development of chronic mechanical allodynia after nerve injuries. Therefore, the purpose of this study was to ascertain the definite neuroimmune interface for these T cells to initiate the development of chronic mechanical allodynia after peripheral nerve injuries. METHODS: First, we utilized both chromogenic and fluorescent immunohistochemistry (IHC) to map αß T cells along the somatosensory pathways for the transmission of mechanical allodynia after modified spared nerve injuries (mSNIs), i.e., tibial nerve injuries, in adult male Sprague-Dawley rats. We further characterized the molecular identity of these αß T cells selectively infiltrating into the leptomeninges of L4 dorsal roots (DRs). Second, we identified the specific origins in lumbar lymph nodes (LLNs) for CD4+ αß T cells selectively present in the leptomeninges of L4 DRs by two experiments: (1) chromogenic IHC in these lymph nodes for CD4+ αß T cell responses after mSNIs and (2) fluorescent IHC for temporal dynamics of CD4+ αß T cell infiltration into the L4 DR leptomeninges after mSNIs in prior lymphadenectomized or sham-operated animals to LLNs. Finally, following mSNIs, we evaluated the effects of region-specific targeting of these T cells through prior lymphadenectomy to LLNs and chronic intrathecal application of the suppressive anti-αßTCR antibodies on the development of mechanical allodynia by von Frey hair test and spinal glial or neuronal activation by fluorescent IHC. RESULTS: Our results showed that during the sub-acute phase after mSNIs, αß T cells selectively infiltrate into the leptomeninges of the lumbar DRs along the somatosensory pathways responsible for transmitting mechanical allodynia. Almost all these αß T cells are CD4 positive. Moreover, the temporal dynamics of CD4+ αß T cell infiltration into the lumbar DR leptomeninges are specifically determined by LLNs after mSNIs. Prior lymphadenectomy to LLNs specifically reduces the development of mSNI-induced chronic mechanical allodynia. More importantly, intrathecal application of the suppressive anti-αßTCR antibodies reduces the development of mSNI-induced chronic mechanical allodynia. In addition, prior lymphadenectomy to LLNs attenuates mSNI-induced spinal activation of glial cells and PKCγ+ excitatory interneurons. CONCLUSIONS: The noteworthy results here provide the first evidence that CD4+ αß T cells selectively infiltrate into the DR leptomeninges of the somatosensory pathways transmitting mechanical allodynia and contribute to the transition from acute to chronic mechanical allodynia after peripheral nerve injuries.

Virtual Screening of Small Molecular Inhibitors against DprE1.

Decaprenylphosphoryl-ß-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We identified potential DprE1 inhibitors from the ChemDiv dataset through virtual screening based on pharmacophore and molecular docking. Thirty selected compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity prediction with the Discovery Studio software package. Two compounds were obtained as hits for inhibiting DprE1 activity in M. tuberculosis and are suitable for further in vitro and in vivo evaluation.

[Helminth derived Immunomodulatory Glycan LNFP3 Impairs Pathogenesis of Peripheral Neuropathic Pain and Spinal Glial Activation].

OBJECTIVES: To investigate the effect of helminth-derived immunomodulatory glycan lacto-N-fucopentaose3(LNFP3) on the pathogenesis of neuropathic pain and spinal glial activation in the corresponding time windows after adult rat tibial nerve permanent transection (modified spared nerve injury, mSNI). METHODS: Ten weeks old male adult Sprague-Dawley (SD) rats weighing 250-300 g were randomly grouped into four groups: sham-operated group (n =6), mSNI group (n =6), mSNI plus bovine serum albumin (BSA) group (n =12) and mSNI plus LNFP3 group (n=12). Rats were subjected to surgical operation or sham operation on the right tibial nerves and were intraperitoneal injected BSA or LNEP3-BSA conjugates by the group design. Animals from each group (n=6 per group) were subjected to the plantar test,von Frey hairs test, pinprick test and acetone test for critical evaluation of region-specific pain responses on the plantar sural and saphenous skin territories of ipsilateral and contralateral hindpaws after injuries. Transverse frozen sections of L3-4 spinal cords from the remaining animals of mSNI plus BSA group and mSNI plus LNFP3 group 7 and 14 d after injury (n=3 for each time point per group)were prepared and subjected to immunofluorescent staining of microglia/macrophage marker [cluster of differentiation molecule 11b (CD11b)] and astrocyte marker [glial fibrillary acidic protein (GFAP)], for analysis of spinal glial activation. RESULTS: After adult rat mSNI, early systematic administration of LNFP3 significantly but not completely attenuated region-specific pathological pain evoked by mechanical and thermal stimuli on the sural and saphenous skin territories of rat hindpaw plantar surfaces in acute (4/5 d after injuries) and subacute (7/8 d and 14/15 d after injuries) phases. Meanwhile, in the ipsilateral spinal cord dorsal horns, this early systematic treatment inhibited microglia/macrophage activation 7 d after injury and astrocyte activation 7 and 14 d after injury. CONCLUSIONS: Early systematic administration of LNFP3 impairs the pathogenesis (acute induction and chronic transition) of neuropathic pain and spinal glial activation in the corresponding time windows after adult rat mSNI.

[Early Systemic Administration of IL-10 Inhibits Neuropathic Pain in Adult Rats with Tibial Nerve Injury].

OBJECTIVES: To determine the effect of early systemic administration of IL-10 on peripheral neuropathic pain induced by tibial nerve permanent transection [modified spared nerve injury (mSNI)]in adult rats. METHODS: Male adult Sprague-Dawley (SD) rats (ten-week old, 250-300 g) with mSNI were randomly divided into mSNI, sham-operated, IL-10 intervention (intraperitoneal injection), PBS intervention (intraperitoneal injection) groups, each containing six rats. Intraperitoneally injections (IL-10 or PBS) were given immediately after surgeries for a single regime with a dosage of 500 uL (0.1 mg/mL). Plantar test, von Frey hairs test, pinprick test and acetone test were performed before and after tibial nerve injuries (0 d, 4/5 d, 7/8 d, 14/15 d) to evaluate region-specific pain responses of the rats on the plantar sural and saphenous skin territories of ipsilateral and contralateral hindpaws. The hindpaw position (on 8 d) of six additional rats with standard SNI was compared with those with mSNI. RESULTS: The rats with standard SNI showed an eversion posture of hindpaws, more prominent than those with mSNI. Region-specific pathological pain evoked by mechanical and thermal stimuli on the sural and saphenous skin territories of the plantar surfaces of rat hindpaws was demonstrated on the ipsilateral rather than contralateral hindpaws. This effect was shown in the rats with mSNI but not in those with sham operations. Compared with PBS, early intraperitoneal injection of IL-10 significantly and persistently attenuated either allodynia or hyperalgesia in the rats with mSNI. CONCLUSIONS: Tibial nerve permanent transection models of adult rats can be used as a simple but useful rodent model of peripheral neuropathic pain. Early systemic administration of IL-10 impairs the pathogenesis of neuropathic pain induced by tibial nerve injuries.

[Senescence-associated Beta Galactosidase Expression in Rat Schwann Cells after Chronic Denervation].

OBJECTIVE: To investigate the effect of prolonged axon depletion on senescence-associated beta galactosidase (SA-ß-gal) expression in Schwann cells (SCs) of adult rats. METHODS: Male adult Sprague-Dawley (SD) rats were randomize grouped into sham-operated group and denervation groups for 1 week, 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks and 8 weeks. Rats were subjected to right sciatic nerve transection. After particular denervation duration for the distal stumps, animals were anesthetized and perfused. Proximal stumps of 5 mm and distal stumps of 10 mm from injured nerves, and the corresponding segments from the sham groups and contralateral nerves were harvested and prepared for SA-ß-gal staining to detect SA-ß-gal expression. Then, additional injured distal stumps denervated for 8 weeks were employed for determining cellular distribution of SA-ß-gal expression by co-labeling of SA-ß-gal and SC-specific protein (S100ß). RESULTS: SA-ß-gal expression transiently increased in distal tips of proximal stumps 2 weeks after adult rat sciatic nerve transection without suture. In contrast, in the distal stumps of transected adult rat sciatic nerves, axon depletion for 2 weeks increased SA-ß-gal expression, and the increased expression of SA-ß-gal remained constant after prolonged denervation durations. Furthermore, combination of SA-ß-gal staining with S100ß immunofluorescence staining showed that SA-ß-gal expression. was exclusively present in denervated SCs. CONCLUSION: Prolonged axon depletion increased SA-ß-gal expression in adult rat SCs.

Transplantation of olfactory ensheathing cells promotes the recovery of neurological functions in rats with traumatic brain injury associated with downregulation of Bad.

BACKGROUND AIMS: The neuroprotective effects of olfactory ensheathing cells (OECs) after transplantation have largely been known in the injured nervous system. However, the underlying mechanisms still must be further elucidated. We explored the effects of OEC transplantation on the recovery of neurophysiologic function and the related anti-apoptosis mechanism in acute traumatic brain injury. METHODS: The OECs from neonatal Sprague-Dawley rats were isolated, identified and labeled and then were immediately transplanted into the regions surrounding the injured brain site that is resulted from free-weight drop injury. RESULTS: Nerve growth factor and it's recepor, p75 was expressed in cultured OECs. Transplanted OECs survived, migrated around the injury site and significantly improved the neurological severe scores compared with the control group (P < 0.05). OEC transplantation significantly increased the number of GAP-43-immunopositive fibers and synaptophysin-positive vesicles (P < 0.05) but significantly decreased the number of apoptotic cells (P < 0.05). On the molecular level, the expression of Bad in the OEC transplantation group was significantly downregulated (P < 0.05). CONCLUSIONS: OEC transplantation could effectively improve neurological deficits in TBI rats; the underlying mechanism may be related with their effects on neuroprotection and regeneration induction, which is associated with the downregulation of the apoptotic molecule Bad.

Discovery of novel urea derivatives as ferroptosis and autophagy inducer for human colon cancer treatment.

A series of novel urea derivatives were designed, synthesized and evaluated for their inhibitory activities against HT-29 cells, and structure-activity relationships (SAR) were summarized. Compound 10p stood out from these derivatives, exhibiting the most potent antiproliferative activity. Further biological studies demonstrated that 10p arrested cell cycle at G2/M phase via regulating cell cycle-related proteins CDK1 and Cyclin B1. The underlying molecular mechanisms demonstrated that 10p induced cell death through ferroptosis and autophagy, but not apoptosis. Moreover, 10p-induced ferroptosis and autophagy were both related with accumulation of ROS, but they were independent of each other. Our findings substantiated that 10p combines ferroptosis induction and autophagy trigger in single molecule, making it a potential candidate for colon cancer treatment and is worth further development.

Neural stem cells grafts decrease neural apoptosis associated with caspase-7 downregulation and BDNF upregulation in rats following spinal cord hemisection.

Transplantation of neural stem cells (NSCs) into lesioned spinal cord demonstrated a beneficial effect for neural repair, the underlying mechanism, however, remains to be elusive. Here, we showed that NSCs, possessing the capacity to differentiate toward into neurons and astrocytes, exhibit a neuroprotective effect by anti-apoptosis mechanism in spinal cord hemi-transected rats despite it did not improve behavior. Intravenous NSCs injection substantially upregulated the level of BDNF mRNA but not its receptor TrkB in hemisected spinal cord, while caspase-7, a downstream apoptosis gene of caspase-3, has been largely down-regulated. TUNEL staining showed that the number of apoptosis cells in injured spinal cord decreased significantly, compared with seen in rats with no NSCs administration. The present finding therefore provided crucial evidence to explain neuroprotective effect of NSCs grafts in hemisected spinal cord, which is associated with BDNF upregulation and caspase-7 downregulation.

One-pot synthesis of 4-methylisoquinolines via a sequential Pd-catalyzed Heck reaction and intramolecular cyclization.

An efficient, one-pot synthesis of 4-methylisoquinolines via a cascade Pd-catalyzed Heck reaction, intramolecular cyclization and isomerization has been developed. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

Design, synthesis and biological evaluation of tetrahydroquinoxaline sulfonamide derivatives as colchicine binding site inhibitors.

Colchicine binding site inhibitors (CBSIs) are potential microtubule targeting agents (MTAs), which can overcome multidrug resistance, improve aqueous solubility and reduce toxicity faced by most MTAs. Novel tetrahydroquinoxaline sulfonamide derivatives were designed, synthesized and evaluated for their antiproliferative activities. The MTT assay results demonstrated that some derivatives exhibited moderate to strong inhibitory activities against HT-29 cell line. Among them, compound I-7 was the most active compound. Moreover, I-7 inhibited tubulin polymerization, disturbed microtubule network, disrupted the formation of mitotic spindle and arrested cell cycle at G2/M phase. However, I-7 didn't induce cell apoptosis. Furthermore, the prediction of ADME demonstrated that I-7 showed favorable physiochemical and pharmacokinetic properties. And the detailed molecular docking confirmed I-7 targeted the site of colchicine through hydrogen and hydrophobic interactions.

Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons.

Amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease. It is axonally transported, endocytosed and sorted to different cellular compartments where amyloid beta (Aß) is produced. However, the mechanism of APP trafficking remains unclear. We present evidence that huntingtin associated protein 1 (HAP1) may reduce Aß production by regulating APP trafficking to the non-amyloidogenic pathway. HAP1 and APP are highly colocalized in a number of brain regions, with similar distribution patterns in both mouse and human brains. They are associated with each other, the interacting site is the 371-599 of HAP1. APP is more retained in cis-Golgi, trans-Golgi complex, early endosome and ER-Golgi intermediate compartment in HAP1-/- neurons. HAP1 deletion significantly alters APP endocytosis and reduces the re-insertion of APP into the cytoplasmic membrane. Amyloid precursor protein-YFP(APP-YFP) vesicles in HAP1-/- neurons reveal a decreased trafficking rate and an increased number of motionless vesicles. Knock-down of HAP1 protein in cultured cortical neurons of Alzheimer's disease mouse model increases Aß levels. Our data suggest that HAP1 regulates APP subcellular trafficking to the non-amyloidogenic pathway and may negatively regulate Aß production in neurons.

Circulating microRNAs are elevated in plasma from severe preeclamptic pregnancies.

Until recently, the molecular pathogenesis of preeclampsia (PE) remained largely unknown. Reports have shown that circulating microRNAs (miRNAs) are promising novel biomarkers for cancer, pregnancy, tissue injury, and other conditions. The objective of this study was to identify differentially expressed miRNAs in plasma from severe preeclamptic pregnancies compared with plasma from normal pregnancies. By mature miRNA microarray analysis, 15 miRNAs, including 13 up- and two downregulated miRNAs, were screened to be differentially expressed in plasma from women with severe PE (sPE). Seven miRNAs, namely miR-24, miR-26a, miR-103, miR-130b, miR-181a, miR-342-3p, and miR-574-5p, were validated to be elevated in plasma from severe preeclamptic pregnancies by real-time quantitative stem-loop RT-PCR analysis. Gene ontology and pathway enrichment analyses revealed that these miRNAs were involved in specific biological process categories (including regulation of metabolic processes, regulation of transcription, and cell cycle) and signaling pathways (including the MAP kinase signaling pathway, the transforming growth factor-ß signaling pathway, and pathways in cancer metastasis). This study presents, for the first time, the differential expression profile of circulating miRNAs in sPE patients. The seven elevated circulating miRNAs may play critical roles in the pathogenesis of sPE, and one or more of them may become potential markers for diagnosing sPE.

Combination of microtubule targeting agents with other antineoplastics for cancer treatment.

Microtubule targeting agents (MTAs) have attracted extensive attention for cancer treatment. However, their clinical efficacies are limited by intolerable toxicities, inadequate efficacy and acquired multidrug resistance. The combination of MTAs with other antineoplastics has become an efficient strategy to lower the toxicities, overcome resistance and improve the efficacies for cancer treatment. In this article, we review the combinations of MTAs with some other anticancer drugs, such as cytotoxic agents, kinases inhibitors, histone deacetylase inhibitors, immune checkpoints inhibitors, to overcome these obstacles. We strongly believe that this review will provide helpful information for combination therapy based on MTAs.

A Distributionally Robust Optimization Method for Passenger Flow Control Strategy and Train Scheduling on an Urban Rail Transit Line.

Regular coronavirus disease 2019 (COVID-19) epidemic prevention and control have raised new requirements that necessitate operation-strategy innovation in urban rail transit. To alleviate increasingly serious congestion and further reduce the risk of cross-infection, a novel two-stage distributionally robust optimization (DRO) model is explicitly constructed, in which the probability distribution of stochastic scenarios is only partially known in advance. In the proposed model, the mean-conditional value-at-risk (CVaR) criterion is employed to obtain a tradeoff between the expected number of waiting passengers and the risk of congestion on an urban rail transit line. The relationship between the proposed DRO model and the traditional two-stage stochastic programming (SP) model is also depicted. Furthermore, to overcome the obstacle of model solvability resulting from imprecise probability distributions, a discrepancy-based ambiguity set is used to transform the robust counterpart into its computationally tractable form. A hybrid algorithm that combines a local search algorithm with a mixed-integer linear programming (MILP) solver is developed to improve the computational efficiency of large-scale instances. Finally, a series of numerical examples with real-world operation data are executed to validate the proposed approaches.

Proteolysis-targeting chimeras for targeting protein for degradation.

Proteolysis-targeting chimeras (PROTACs) are an emerging tool for therapeutic intervention by reducing or eliminating disease-causing proteins. PROTACs are bifunctional molecules that consist of a target protein ligand, a linker and an E3 ligase ligand, which mediate the polyubiquitination of the target protein, ultimately leading to the target protein degradation by the ubiquitin-proteasome pathway. We review some of the main PROTACs that have been reported recently and discuss their potential therapeutic benefits over classical enzyme inhibition. Future research is expected to focus on the delivery and bioavailability of PROTACs due to their high molecular weight (700-1000 Da).