Advances and prospects in targeted protein degradation / 药学实践杂志

Targeted protein degradation (TPD) techniques eliminate pathogenic proteins by hijacking the intracellular proteolysis machinery which includes the ubiquitin-proteasome system (UPS) and the lysosomal degradation pathway, holding promise to overcome the limitations of traditional inhibitors and further broaden the target space including many “undruggable” targets, and provide new targeted treatments for drug discovery. In this review, recent advances in a variety of promising TPD strategies were summarized, such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera AUTAC and AUTOTAC, particularly. The representative case studies, potential applications and challenges were analyzed.

Design, synthesis and degradation activity of BRD4-targeting ATTECs / 药学实践杂志

Objective To design and synthesize autophagic degraders targeting BRD4 based on autophagosome tethering compound (ATTEC) strategy and test their BRD4 degradation activity. Methods BRD4-targeting ATTECs were constructed by conjugating ispinesib that used as a LC3 ligand and JQ1 through a variety of alkane linkers. The final compounds were confirmed by 1H NMR, 13C NMR and ESI-MS, and their degradation activity in different cell lines were tested by Western Blot. Results Five BRD4-ATTEC molecules were successfully synthesized for the first time. Compound 4 showed moderate BRD4 degradation activity in different cell lines. Conclusion The novel BRD4 autophagic degraders were discovered, which expanded the applicability of targeted autophagic degradation via ATTEC.

Controlling antifungal activity with light: Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 μg/mL) could be efficiently recovered (MIC80 = 0.5-8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

Antifungal activity study on HDAC inhibitor Rocilinostat / 药学实践杂志

Objective To evaluate the in vitro synergistic antifungal activity of HDAC inhibitors in combination with azole drugs against azoles-resistant Candida strains. Methods The checkerboard microdilution method was used to evaluate the antifungal activity of the HDAC inhibitors in combination with azole drugs against clinically drug-resistant strains. The fungistatic activity and toxicity of Rocilinostat was determined through time-growth curve assay and cytotoxicity assay. Results The compound Rocilinostat combined with azole drugs showed excellent synergistic antifungal activity against a variety of azoles-resistant Candida albicans and Candida glabrata. The combination of high concentration Rocilinostat with FLC exhibited fungistatic effects. Very low toxicity was detected with Rocilinostat towards normal cells. Rocilinostat showed better HDAC inhibitory activity than SAHA. Conclusion As a fungi HDAC inhibitor, Rocilinostat has excellent in vitro synergistic antifungal activity and no severe toxicity to normal human cells.

Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

KRAS‒PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (K D = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDEδ interaction.

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin-proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.

Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC

Disciplinary system and classification of military pharmacy / 药学实践杂志

Objective To discuss the system and classification of military pharmacy disciplines. Methods Based on the analysis and induction of the military pharmacy subject positioning, classification status, classification ideas and classification methods, the military pharmacy subject system is described with system analysis and system structured approach. Results The military pharmacy disciplinary system may be divided into four major categories: military pharmacy science, military pharmacy technology, military pharmacy engineering, and military pharmacy management, and several sub-categories. Conclusion Strengthening the research of military pharmacy disciplinary system will improve the disciplinary system classification, which will help improve the overall cognitive level of military pharmacy discipline and accelerate the development of military pharmacy disciplinary system.

Recommendations for prevention and treatment of device-related pressure injuries during COVID-19 period / 药学实践杂志

With the outbreak of COVID-19, non-stop working medical staff need to wear protective equipment for a long time, which could easily cause device-related pressure injuries to nose, cheek, forehead or the back of auricle, and might even cause facial skin swelling and ulceration. The above problems reduce work efficiency and increase the infection risk for healthcare people. This article introduces the concept of device-related pressure injuries and summarizes the progress of the treatment for device-related pressure injuries at home and abroad in recent years, aiming at providing guidance for frontline medical staff to prevent device-related pressure injuries.

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent and antitumor potency. Particularly, compound was orally active and possessed excellent antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, .) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

Novel fluorescent probes of 10-hydroxyevodiamine: autophagy and apoptosis-inducing anticancer mechanisms

Natural product evodiamine and its derivatives represent a promising class of multi-target antitumor agents. However, the clinical development of these compounds has been hampered by a poor understanding of their antitumor mechanisms. To tackle this obstacle, herein, novel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine. This compound was proven to be distributed in the mitochondria and lysosomes and to act by autophagy and apoptosis mechanisms.

Structural simplification: an efficient strategy in lead optimization

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

The construction of pharmacophore model for(1,3)-β-D-glucan synthase small molecule inhibitors / 药学实践杂志

Objective To perform the ligand-based computer-aided drug design and construct the pharmacophore model of(1,3)-β-D-Glucan Synthase(GS)small molecule inhibitors.Method Six small molecules with diverse structures and good inhibitory activity were selected to construct the training set.The HipHop algorithm in Catalyst pharmacophore generation module was utilized to construct the pharmacophore models.The pharmacophore models were evaluated by constructed Decoy-set 3D database.Results Pharmacophore 02 has a good enrichment factor,sensitivity and specificity parameters.Pharmacoph-ore model validation with Decoyset 3D database proved that the model has good distinguishing capability.Conclusion The pharmacophore model of GS small molecule inhibitors was constructed and tested.It will provide valuable information for de-sign and discovery of novel small molecule GS inhibitors.

Design and synthesis of photosensitizer,13,15-cycloimides chlorin p6 / 药学实践杂志

Objective To design and prepare 13 ,15-cycloimides chlorin p6 (1) ,a class of chlorin related antitumor photo-sensitizers ,which contain a more stable six-membered cyclic imide comparing to the exocyclic anhydride ring of purpurin-18 (2) .Compounds (1) exhibit strong absorption at long wavelengths near λmax 700 nm to take full advantage of greater tissue penetration .Methods Pheophorbide a (3) was obtained by acid hydrolysis of chlorophyll a ,which was from crude chlorophyll extracts of Chinese traditional herb named Silkworm excrement .Purpurin-18 (2) was prepared by air oxidation and alkali open loop simultaneously on five-membered beta-keto carboxylic ester ring of pheophorbide a (3) .Finally ,the target compounds 1a~1j were synthesized via condensation of its anhydride ring with various amines including carboxyl-protected amino acids . Results Target compounds 1a~1j were successfully synthesized in yields ranged from 32 .6% to 65 .2% .Their structures were confirmed by elemental analysis ,ESI-MS and 1 H NMR spectra .Conclusion Treatment of purpurin-18 (2) with amines can produce target compounds 1a~1j .The starting raw material was inexpensive and readily available .The reaction conditions were mild and workup was convinient .

Optimization of synthesis process of photosensitizer chlorin f / 药学实践杂志

Objective To improve the synthesis process of chlorine f (1).Methods A "one-pot"method was applied to prepare Photosensitizer component (1),using pheophorbide a (3) as raw material by oxidating and cracking of the E-ring of (3) with bubbling oxygen in alcoholic solution of potassium hydroxide at 0 ℃ followed by refluxing in nitrogen atmosphere.In order to obtain the optimal synthetic procedure,the orthogonal experimental design of L9 (34 ) was adopted to investigate three different levels of four main factors i.e.ring opening reaction time,alcoholic variety,alkali concentration and refluxing reaction time.Results The target compound (1) was optimizedly synthesized through treatment of raw material (3) with bubbling oxy-gen in 25% ethanol solution of potassium hydroxide at 0℃ for 30 min,followed by refluxing in nitrogen atmosphere for 20 min in yield of 40.8%.Conclusion The procedure developed has some advantages of simple and safty operation,and high synthetic yield.

Advances of validation of bioactive small molecule targets / 药学实践杂志

With the development of science and the progress of age,medicinal chemistry is not only limited to the lead discovery and the structure-activity relationship studies,but also finding the target of bioactive small molecule drugs has be-come a tough issue to be solved.The identification and validation of bioactive small molecule targets has become the most criti-cal and difficult task,which plays a decisive role in academic and pharmaceutical research.Herein we summarize the current methods for target identification of small molecules,and mainly discuss about the target identification method by the chemical probes.Recent cases of successful application were also introduced to demonstrate the strategy of probe synthesis and design.

Research progress of dual topoisomerase Ⅰ and Ⅱ inhibitors / 药学实践杂志

DNA topoisomerases (Tops) are essential enzymes that regulate the cellular processes such as replication , transcription ,recombination and repair .DNA Tops can be classified into two types ,topoisomerase Ⅰ (TopⅠ ) and topoi-somerase Ⅱ (TopⅡ) .They catalyze the breakage and religation of DNA ,maintaining the topological changes of DNA and va-rious DNA metabolic processes .Due to their important role in DNA metabolism ,the ability to interfere with the functions of Tops or generating Top-mediated DNA damage is an effective strategy for cancer chemotherapy .Tops have been considered as the most important targets for tumor chemotherapy .In this review ,we used examples to describe the development of dual to-poisomerase Ⅰ and Ⅱ inhibitors .

Recent advances of tyrosyl-DNA phosdiesterase Ⅰ (TdpⅠ) inhibitors / 药学实践杂志

Tyrosyl-DNA phosphodiesterase Ⅰ (TdpⅠ ) is a recently discovered proteinthat catalyzes the hydrolysis of 3′-phosphotyrosyl bonds .Such linkages form in vivo during the interaction of DNA and topoisomerase Ⅰ (TopⅠ) .TdpⅠ has been regarded as a potential therapeutic co-target of TopⅠ because it has the functions of repairing Top Ⅰ compound and coun-teracting the effects of Top Ⅰ inhibitors .TdpⅠ inhibitors can not only synergizing with Top Ⅰ-targeting drugs (camptoth-ecins) ,but also strength the function of bleomycin ,topoisomerase Ⅱ (TopⅡ ) inhibitors (etoposide ,doxorubicin) and DNA alkylating agents .We summarized the researching advance of TdpⅠ inhibitors and focused on the introduction of the mecha-nism ,bioactivity and structure-activity relationship .

Advance in anti-cancer lead-compounds derived from natural products / 药学实践杂志

Cancer is a serious threat to human life and health .Therefore, there is an emergent need to develop novel anti-cancer agents with new structural type , new mechanism of action and higher efficacy .Natural products had played a key role in the dis-covery of anticancer agents .The anti-cancer activity , mechanism of action , structure and activity relationship of several lead-com-pounds which were derived from natural products were summarized in this review .

Recent advances in the study of new antifungal lead compounds / 药学学报

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.